Indanylaminopyridylcyclopropanecarboxylic acids, pharmaceutical compositions and uses thereof

ABSTRACT

The present invention relates to compounds of general formula I, 
                         
wherein the groups R, R 1 , R 2 , R 3 , m and n are as defined herein, which compounds have valuable pharmacological properties, in particular their ability to bind to the GPR40 receptor and modulate its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular type 2 diabetes. Furthermore, the invention relates to novel intermediates, useful for the synthesis of compounds of formula I.

FIELD OF THE INVENTION

The present invention relates to novelindanylaminopyridylcyclopropanecarboxylic acids, that are agonists ofthe G-protein coupled receptor 40 (GPR40, also known as free fatty acidreceptor FFAR 1), to processes for their preparation, to pharmaceuticalcompositions containing these compounds and to their medical use for theprophylaxis and/or treatment of diseases which can be influenced by themodulation of the function of GPR40. Particularly, the pharmaceuticalcompositions of the invention are suitable for the prophylaxis and/ortherapy of metabolic diseases, such as diabetes, more specifically type2 diabetes mellitus, and conditions associated with the disease,including insulin resistance, obesity, cardiovascular disease anddyslipidemia.

BACKGROUND OF THE INVENTION

Metabolic diseases are diseases caused by an abnormal metabolic processand may either be congenital due to an inherited enzyme abnormality oracquired due to a disease of an endocrine organ or failure of ametabolically important organ such as the liver or the pancreas.

Diabetes mellitus is a disease state or process derived from multiplecausative factors and is defined as a chronic hyperglycemia associatedwith resulting damages to organs and dysfunctions of metabolicprocesses. Depending on its etiology, one differentiates between severalforms of diabetes, which are either due to an absolute (lacking ordecreased insulin secretion) or to a relative lack of insulin. Diabetesmellitus Type I (IDDM, insulin-dependent diabetes mellitus) generallyoccurs in adolescents under 20 years of age. It is assumed to be ofauto-immune etiology, leading to an insulitis with the subsequentdestruction of the beta cells of the islets of Langerhans which areresponsible for the insulin synthesis. In addition, in latent autoimmunediabetes in adults (LADA; Diabetes Care. 8: 1460-1467, 2001) beta cellsare being destroyed due to autoimmune attack. The amount of insulinproduced by the remaining pancreatic islet cells is too low, resultingin elevated blood glucose levels (hyperglycemia). Diabetes mellitus TypeII generally occurs at an older age. It is above all associated with aresistance to insulin in the liver and the skeletal muscles, but alsowith a defect of the islets of Langerhans. High blood glucose levels(and also high blood lipid levels) in turn lead to an impairment of betacell function and to an increase in beta cell apoptosis.

Persistent or inadequately controlled hyperglycemia is associated with awide range of pathologies. Diabetes is a very disabling disease, becausetoday's common antidiabetic drugs do not control blood sugar levels wellenough to completely prevent the occurrence of high and low blood sugarlevels. Out of range blood sugar levels are toxic and cause long-termcomplications for example retinopathy, renopathy, neuropathy andperipheral vascular disease. There is also a host of related conditions,such as obesity, hypertension, stroke, heart disease and hyperlipidemia,for which persons with diabetes are substantially at risk.

Obesity is associated with an increased risk of follow-up diseases suchas cardiovascular diseases, hypertension, diabetes, hyperlipidemia andan increased mortality. Diabetes (insulin resistance) and obesity arepart of the “metabolic syndrome” which is defined as the linkage betweenseveral diseases (also referred to as syndrome X, insulin-resistancesyndrome, or deadly quartet). These often occur in the same patients andare major risk factors for development of diabetes type II andcardiovascular disease. It has been suggested that the control of lipidlevels and glucose levels is required to treat diabetes type II, heartdisease, and other occurrences of metabolic syndrome (see e.g., Diabetes48: 1836-1841, 1999; JAMA 288: 2209-2716, 2002).

The free fatty acid receptor GPR40 (also referred to as either FFAR,FFAR1, or FFA1) is a cell-surface receptor and a member of the genesuperfamily of G-protein coupled receptors, which was first identifiedas a so-called orphan receptor, i.e. a receptor without a known ligand,based on the predicted presence of seven putative transmembrane regionsin the corresponding protein (Sawzdargo et al. (1997) Biochem. Biophys.Res. Commun. 239: 543-547). GPR40 is found to be highly expressed inseveral particular cell types: the pancreatic β cells andinsulin-secreting cell lines, as well as in enteroendocrine cells, tastecells, and is reported to be expressed in immune cells, splenocytes, andin the human and monkey brain. Meanwhile, fatty acids of varying chainlengths are thought to represent the endogenous ligands for GPR40,activation of which is linked primarily to the modulation of the Gqfamily of intra-cellular signaling G proteins and concomitant inductionof elevated calcium levels, although activation of Gs- and Gi-proteinsto modulate intracellular levels of cAMP have also been reported. GPR40is activated especially by long-chain FFA, particularly oleate, as wellas the PPAR-gamma agonist rosiglitazone.

It has been recognized that the fatty acids that serve as activators forGPR40 augment the elevated plasma glucose-induced secretion of insulinthrough GPR40 receptors that are expressed in the insulin secretingcells (Itoh et al. (2003) Nature 422: 173-176; Briscoe et al. (2003) J.Biol. Chem. 278: 11303-11311; Kotarsky et al. (2003) Biochem. Biophys.Res. Commun. 301: 406-410). Despite initial controversy, the use ofGPR40 agonist appears to be the appropriate for increasing insulinrelease for the treatment of diabetes (see e.g. Diabetes 2008, 57, 2211;J. Med. Chem. 2007, 50, 2807). Typically, long term diabetes therapyleads to the gradual diminution of islet activity, so that afterextended periods of treatment Type 2 diabetic patients need treatmentwith daily insulin injections instead. GPR40 agonists may have thepotential to restore or preserve islet function, therefore, GPR40agonists may be beneficial also in that that they may delay or preventthe diminution and loss of islet function in a Type 2 diabetic patient.

It is well established that the incretins GLP-1 (glucagon-likepeptide-1) and GIP (glucose-dependent insulinotropic peptide; also knownas gastric inhibitory peptide) stimulate insulin secretion and arerapidly inactivated in vivo by DPP-4. These peptidyl hormones aresecreted by endocrine cells that are located in the epithelium of thesmall intestine. When these endocrine cells sense an increase in theconcentration of glucose in the lumen of the digestive tract, they actas the trigger for incretin release. Incretins are carried through thecirculation to beta cells in the pancreas and cause the beta cells tosecrete more insulin in anticipation of an increase of blood glucoseresulting from the digesting meal. Further studies indicating that theGPR40 modulatory role on the release of incretins from theenteroendocrine cells, including CCK, GLP-1, GIP, PYY, and possiblyothers, suggest that GPR40 modulators may contribute to enhanced insulinrelease from the pancreatic beta cells also indirectly by e.g. asynergistic effect of GLP-1 and possibly GIP on the insulin release, andthe other release incretins may also contribute to an overall beneficialcontribution of GPR40 modulation on metabolic diseases. The indirectcontributions of GPR40 modulation on insulin release through theelevation of plasma levels of incretins may be further augmented by thecoadministration of inhibitors of the enzymes responsible for theincretin degradation, such as inhibitors of DPP-4.

Insulin imbalances lead to conditions such as type II diabetes mellitus,a serious metabolic disease. The modulation of the function of GPR40 inmodulating insulin secretion indicates the therapeutic agents capable ofmodulating GPR40 function could be useful for the treatment of disorderssuch as diabetes and conditions associated with the disease, includinginsulin resistance, obesity, cardiovascular disease and dyslipidemia.

OBJECT OF THE PRESENT INVENTION

The object of the present invention is to provide new compounds,hereinafter described as compounds of formula I, in particular newindanylaminopyridylcyclopropanecarboxylic acids, which are active withregard to the G-protein-coupled receptor GPR40, notably are agonists ofthe G-protein-coupled receptor GPR40.

A further object of the present invention is to provide new compounds,in particular new indanylaminopyridylcyclopropanecarboxylic acids, whichhave an activating effect on the G-protein-coupled receptor GPR40 invitro and/or in vivo and possess suitable pharmacological andpharmacokinetic properties to use them as medicaments.

A further object of the present invention is to provide effective GPR40agonists, in particular for the treatment of metabolic disorders, forexample diabetes, dyslipidemia and/or obesity.

A further object of the present invention is to provide methods fortreating a disease or condition mediated by the activation theG-protein-coupled receptor GPR40 in a patient.

A further object of the present invention is to provide a pharmaceuticalcomposition comprising at least one compound according to the invention.

A further object of the present invention is to provide a combination ofat least one compound according to the invention with one or moreadditional therapeutic agents.

Further objects of the present invention become apparent to the oneskilled in the art by the description hereinbefore and in the followingand by the examples.

GPR40 modulators are known in the art, for example, the compoundsdisclosed in WO 2004/041266 (EP 1 559 422), WO 2007/033002, WO2009/157418, and WO 2013/178575. Theindanylaminopyridylcyclopropanecarboxylic acids of the present inventionmay provide several advantages, such as enhanced potency, high metabolicand/or chemical stability, high selectivity and tolerability, enhancedsolubility, and the possibility to form stable salts.

SUMMARY OF THE INVENTION

In a first aspect, the invention relates to a compound of formula

wherein

-   R is selected from the group R-G1 consisting of    -   H, F, Cl, Br, I, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,        C₃₋₆-cycloalkyl, NC—, HNR^(N)—C(═O)—, C₁₋₄-alkyl-NR^(N)—C(═O)—,        C₃₋₆-cycloalkyl-NR^(N)—C(═O)—, heterocyclyl-NR^(N)—C(═O)—,        heteroaryl-NR^(N)—C(═O)—, HOOC—, C₁₋₄-alkyl-O—C(═O)—, O₂N—,        HR^(N)N—, C₁₋₄-alkyl-R^(N)N—, C₁₋₄-alkyl-C(═O)NR^(N)—,        C₃₋₆-cycloalkyl-C(═O)NR^(N)—, heterocyclyl-C(═O)—NR^(N)—,        heteroaryl-C(═O)NR^(N)—, C₁₋₄-alkyl-S(═O)₂NR^(N)—,        C₃₋₆-cycloalkyl-S(═O)₂NR^(N)—, heterocyclyl-S(═O)₂NR^(N)—,        heteroaryl-S(═O)₂NR^(N)—, HO—, C₁₋₆-alkyl-O—,        HOOC—C₁₋₃-alkyl-O—, heterocyclyl-C₁₋₃-alkyl-O—,        phenyl-C₁₋₃-alkyl-O—, C₃₋₆-cycloalkyl-O—, heterocyclyl-O—,        heteroaryl-O—, C₁₋₄-alkyl-S—, C₃₋₆-cycloalkyl-S—,        heterocyclyl-S—, C₁₋₄-alkyl-S(═O)—, C₃₋₆-cycloalkyl-S(═O)—,        heterocyclyl-S(═O)—, C₁₋₄-alkyl-S(═O)₂—,        C₃₋₆-cycloalkyl-S(═O)₂—, heterocyclyl-S(═O)₂—, phenyl-S(═O)₂—,        heteroaryl-S(═O)₂—, HNR^(N)—S(═O)₂—, C₁₋₄-alkyl-NR^(N)—S(═O)₂—,        heterocyclyl, phenyl, and heteroaryl,        -   wherein each alkyl, cycloalkyl, and heterocyclyl group or            sub-group within the groups forming R is optionally            substituted with 1 or more F atoms and optionally            substituted with 1 to 3 groups independently selected from            Cl, C₁₋₃-alkyl, NC—, (R^(N))₂N—, HO—, C₁₋₃-alkyl-O—, and            C₁₋₃-alkyl-S(═O)₂—; and        -   wherein each phenyl and heteroaryl group or sub-group within            the groups forming R is optionally substituted with 1 to 5            substituents independently selected from F, Cl, C₁₋₃-alkyl,            HF₂C—, F₃C—, NC—, (R^(N))₂N—, HO—, C₁₋₃-alkyl-O—, F₃C—O—,            and C₁₋₃-alkyl-S(═O)₂—;        -   wherein each heterocyclyl group or sub-group within the            groups forming R is selected from            -   a cyclobutyl group wherein 1 CH₂ group is replaced by                —NR^(N)— or —O—;            -   a C₅₋₆-cycloalkyl group wherein 1 CH₂ group is replaced                by —C(═O)—, —NR^(N)—, —O—, —S—, or —S(═O)₂— and/or 1 CH                group is replaced by N;            -   a C₅₋₆-cycloalkyl group wherein 1 CH₂ group is replaced                by —NR^(N)— or —O—, a second CH₂ group is replaced by                —NR^(N)—, —C(═O)— or —S(═O)₂— and/or 1 CH group is                replaced by N; and            -   a C₅₋₆-cycloalkyl group wherein 2 CH₂ groups are                replaced by —NR^(N)— or 1 CH₂ group by —NR^(N)— and the                other by —O— and a third CH₂ group is replaced by                —C(═O)— or —S(═O)₂— and/or 1 CH group is replaced by N;        -   wherein each heteroaryl group or sub-group within the groups            forming R is selected from            -   tetrazolyl and a 5- or 6-membered heteroaromatic ring                which contains 1, 2, or 3 heteroatoms independently of                each other selected from ═N—, —NR^(N)—, —O—, and —S—,                wherein in heteroaromatic groups containing a —HC═N—                unit this group is optionally replaced by                —NR^(N)—C(═O)—;        -   wherein in heteroaryl and heterocyclyl rings with one or            more NH groups, each of said NH groups is replaced by            NR^(N);-   R¹ is selected from the group R¹-G1 consisting of H, F, Cl,    C₁₋₄-alkyl, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkyl,    C₁₋₄-alkyl-O—C₁₋₄-alkyl, NC—, HO—, C₁₋₄-alkyl-O—,    C₃₋₆-cycloalkyl-O—, C₁₋₄-alkyl-S—, C₁₋₄-alkyl-S(O)—, and    C₁₋₄-alkyl-S(O)₂—,    -   wherein any alkyl and cycloalkyl group or sub-group within the        groups forming R¹ is optionally substituted with 1 or more F        atoms, and wherein multiple R¹ may be identical or different if        m is 2, 3 or 4;-   m is an integer selected from 1, 2, 3, and 4;-   R² is selected from the group R²-G1 consisting of H, F, Cl,    C₁₋₄-alkyl, NC—, and C₁₋₄-alkyloxy,    -   wherein any alkyl group or sub-group within the groups forming        R² is optionally substituted with 1 or more F atoms, and wherein        multiple R² may be identical or different if n is 2 or 3;-   R³ is selected from the group R³-G1 consisting of H, F, Cl,    C₁₋₄-alkyl, NC—, and C₁₋₄-alkyl-O—,    -   wherein each alkyl group or sub-group within the groups forming        R³ is optionally substituted with 1 or more F atoms;-   n is an integer selected from 1, 2, and 3;-   R^(N) is independently of each other selected from the group    R^(N)-G1 consisting of H, C₁₋₄-alkyl, HO—C₁₋₄-alkyl-(H₂C)—,    C₁₋₃-alkyl-O—C₁₋₄-alkyl-, C₁₋₄-alkyl-C(═O)—, C₁₋₄-alkyl-NH—C(═O)—,    C₁₋₄-alkyl-N(C₁₋₄-alkyl)-C(═O)—, C₁₋₄-alkyl-O—C(═O)—, and    C₁₋₄-alkyl-S(═O)₂—,    -   wherein each alkyl group or sub-group within the groups forming        R^(N) is optionally substituted with 1 or more F atoms;        wherein in any definition mentioned hereinbefore and if not        specified otherwise, any alkyl group or sub-group may be        straight-chained or branched,        the isoforms, tautomers, stereoisomers, metabolites, prodrugs,        solvates, hydrates, and the salts thereof, particularly the        physiologically acceptable salts thereof with inorganic or        organic acids or bases, or the combinations thereof.

The extension -Gn used within the definitions is meant to identify genusn of the respective substituent. For example, R-G1 defines genus 1 ofthe substituent R.

The expression “optionally substituted with 1 or more F atoms” meansthat none or one up to successively all H atoms bound to carbon atoms ofthe respective group or submoiety may be replaced by F atoms, preferably1 to 5 H atoms or, more preferred, 1 to 3 H atoms may be replaced by Fatoms.

In a further aspect this invention relates to a pharmaceuticalcomposition, comprising one or more compounds of general formula I orone or more pharmaceutically acceptable salts thereof according to theinvention, optionally together with one or more inert carriers and/ordiluents.

In a further aspect this invention relates to a method for treatingdiseases or conditions which are mediated by activating theG-protein-coupled receptor GPR40 in a patient in need thereofcharacterized in that a compound of general formula I or apharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the invention, there is provided a methodfor treating a metabolic disease or disorder, such as diabetes,dyslipidemia and/or obesity, in a patient in need thereof characterizedin that a therapeutically effective amount of a compound of generalformula I or a pharmaceutically acceptable salt thereof is administeredto the patient.

According to another aspect of the invention, there is provided the useof a compound of the general formula I or a pharmaceutically acceptablesalt thereof for the manufacture of a medicament for a therapeuticmethod as described hereinbefore and hereinafter.

According to another aspect of the invention, there is provided acompound of the general formula I or a pharmaceutically acceptable saltthereof for use in a therapeutic method as described hereinbefore andhereinafter.

In a further aspect this invention relates to a method for treating adisease or condition mediated by the activation of the G-protein-coupledreceptor GPR40 in a patient that includes the step of administering tothe patient in need of such treatment a therapeutically effective amountof a compound of the general formula I or a pharmaceutically acceptablesalt thereof in combination with a therapeutically effective amount ofone or more additional therapeutic agents.

In a further aspect this invention relates to the use of a compound ofthe general formula I or a pharmaceutically acceptable salt thereof incombination with one or more additional therapeutic agents for thetreatment of diseases or conditions which are mediated by the activationof the G-protein-coupled receptor GPR40.

In a further aspect this invention relates to a pharmaceuticalcomposition which comprises a compound according to general formula I ora pharmaceutically acceptable salt thereof and one or more additionaltherapeutic agents, optionally together with one or more inert carriersand/or diluents.

Other aspects of the invention become apparent to the one skilled in theart from the specification and the experimental part as describedhereinbefore and hereinafter.

DETAILED DESCRIPTION

Unless otherwise stated, the groups, residues, and substituents,particularly R, R¹, R², R³, m and n are defined as above andhereinafter. If residues, substituents, or groups occur several times ina compound, they may have the same or different meanings. Some preferredmeanings of individual groups and substituents of the compoundsaccording to the invention will be given hereinafter. Any and each ofthese definitions may be combined with each other.

R:

R-G1:

The group R is preferably selected from the group R-G1 as definedhereinbefore.

R-G2:

In another embodiment the group R is selected from the group R-G2consisting of

-   -   H, F, Cl, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, NC—, HNR^(N)—C(═O)—,        C₁₋₄-alkyl-NR^(N)—C(═O)—, C₃₋₆-cycloalkyl-NR^(N)—C(═O)—,        heterocyclyl-NR^(N)—C(═O)—, HOOC—, HR^(N)N—, C₁₋₄-alkyl-R^(N)N—,        C₁₋₄-alkyl-C(═O)NR^(N)—, C₃₋₆-cycloalkyl-C(═O)NR^(N)—,        heterocyclyl-C(═O)NR^(N)—, C₁₋₄-alkyl-S(═O)₂NR^(N)—, HO—,        C₁₋₆-alkyl-O—, HOOC—(C₁₋₂-alkyl)-O—, heterocyclyl-C₁₋₂-alkyl-O—,        phenyl-C₁₋₂-alkyl-O—, C₃₋₆-cycloalkyl-O—, heterocyclyl-O—,        heteroaryl-O—, C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl-S(═O)₂—,        heterocyclyl-S(═O)₂—, HNR^(N)—S(═O)₂—,        C₁₋₄-alkyl-NR^(N)—S(═O)₂—, heterocyclyl, and heteroaryl,        -   wherein each alkyl, cycloalkyl, and heterocyclyl group or            sub-group within the groups forming R is optionally            substituted with 1 or more F atoms and optionally            substituted with 1 to 2 groups independently selected from            Cl, H₃C—, NC—, R^(N)HN—, HO—, H₃C—O—, and H₃C—S(═O)₂—;        -   wherein each heteroaryl group or sub-group within the groups            forming R is optionally substituted with 1 to 3 substituents            independently selected from F, Cl, H₃C—, F₃C—, NC—,            (R^(N))₂N—, HO—, H₃C—O—, F₃C—O—, and H₃C—S(═O)₂—;        -   wherein each heterocyclyl group or sub-group within the            groups forming R is selected from            -   a cyclobutyl group wherein 1 CH₂ group is replaced by                —NR^(N)— or —O—;            -   a C₅₋₆-cycloalkyl group wherein 1 CH₂ group is replaced                by —C(═O)—, —NR^(N)—, —O— or —S(═O)₂— and/or 1 CH group                is replaced by N;            -   a C₅₋₆-cycloalkyl group wherein 1 CH₂ group is replaced                by —NR^(N)— or —O—, a second CH₂ group is replaced by                —NR^(N)—, —C(═O)— or —S(═O)₂— and/or 1 CH group is                replaced by N;        -   wherein each heteroaryl group or sub-group within the groups            forming R is selected from            -   tetrazolyl, a 5-membered heteroaromatic ring which                contains 1, 2 or 3 heteroatoms independently of each                other selected from ═N—, —NH—, O and S, and a 6-membered                heteroaromatic ring which contains 1 or 2 ═N— atoms,                wherein a —HC═N— unit is optionally replaced by                —NH—C(═O)—;        -   and wherein in each of the above heteroaryl and heterocyclyl            group or sub-group containing one or more NH, said group(s)            is replaced by NR^(N).

R-G3:

In another embodiment the group R is selected from the group R-G3consisting of H, F, Cl, C₁₋₄-alkyl, C₃-cycloalkyl, NC—, H₂N—C(═O)—,HOOC—, H₂N—, C₁₋₄-alkyl-S(═O)₂NR^(N)—, HO—, C₁₋₅-alkyl-O—, HOOC—CH₂—O—,heterocyclyl-CH₂—O—, C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, heteroaryl-O—,heterocyclyl-S(═O)₂—, heterocyclyl, and heteroaryl,

-   -   wherein each alkyl, cycloalkyl, and heterocyclyl group or        sub-group within the groups forming R is optionally substituted        with 1 or more F atoms and optionally substituted with 1 group        selected from Cl, H₃C—, NC—, R^(N)HN—, HO—, H₃C—O—, and        H₃C—S(═O)₂—;    -   wherein each heteroaryl group or sub-group within the groups        forming R is optionally substituted with 1 to 2 substituents        independently selected from F, Cl, H₃C—, F₃C—, (R^(N))₂N—, HO—,        H₃C—O—, F₃C—O—, and H₃C—S(═O)₂—;    -   wherein each heterocyclyl or sub-group within the groups forming        R is selected from a cyclobutyl group wherein 1 CH₂ group is        replaced by —NR^(N)— or —O—; a C₅₋₆-cycloalkyl group wherein 1        CH₂ group is replaced by —C(═O)—, —NR^(N)—, —O— or —S(═O)₂—        and/or 1 CH group is replaced by N;    -   wherein each heteroaryl group or sub-group within the groups        forming R is selected from tetrazolyl, a 5-membered        heteroaromatic ring which contains 1, 2 or 3 heteroatoms        independently of each other selected from ═N—, —NH—, O and S,        and a 6-membered heteroaromatic ring which contains 1 or 2 ═N—        atoms, wherein a —HC═N— unit is optionally replaced by        —NH—C(═O)—;    -   and wherein in each heteroaryl and heterocyclyl group or        sub-group mentioned under R-G3 containing one or more NH, said        group(s) is replaced by NR^(N).

R-G4:

According to another embodiment the group R is selected from the groupR-G4 consisting of:

H, F, Cl, H₂NO(═O)—, H₃CNH—C(═O)—, (H₃C)₂N—C(═O)—, HOOC—;

C₁₋₃-alkyl optionally substituted with 1 or more F or optionallymonosubstituted with HO—;

cyclopropyl optionally monosubstituted with NC—;

H₃C—O— optionally monosubstituted with C₁₋₄-alkyl, HOOC—, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, or 1,1-dioxotetrahydrothiopyranyl,

-   -   wherein the C₁₋₄-alkyl group optionally attached to H₃C—O— is        optionally monosubstituted with NC—, HO— or H₃C—S(═O)₂—, and    -   wherein said oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and        1,1-dioxotetrahydrothiopyranyl groups are optionally        monosubstituted with H₃C— or HO—;

tetrahydrofuranyl-O— optionally monosubstituted with HO—;tetrahydropyranyl-O—; and

a heteroaryl group selected from pyrazolyl, [1,3,4]oxadiazolyl,tetrazolyl, pyridyl, pyridin-2-onyl, pyrazinyl, pyrimidinyl,pyrimidin-2-onyl, and pyrimidin-4-onyl,

-   -   wherein each of said heteroaryl groups is optionally        monosubstituted with H₃C— or H₃C—O—, and    -   wherein each H—N group in said heteroaryl groups is optionally        replaced with H₃C—N or (H₃C)₂C(OH)—H₂C—N.

R-G5:

In another embodiment the group R is selected from the group R-G5consisting of F, Cl, H₃C—, H₃C—H₂C—, (H₃C)₂CH—,

F₃C—, HOCH₂—, H₂N—C(═O)—, H₃C—NH—C(═O)—, (H₃C)₂N—C(═O)—, HOOC—, H₃C—O—,

wherein the asterisk (-*) indicates the site/point of attachment.

R-G6:

In another embodiment the group R is selected from the group R-G6consisting of

wherein the asterisk (-*) indicates the site/point of attachment.

R¹:

R¹-G1:

The group R¹ is preferably selected from the group R¹-G1 as definedhereinbefore.

R¹-G2:

According to one embodiment the group R¹ is selected from the groupR¹-G2 consisting of H, F, Cl, C₁₋₃-alkyl, cyclopropyl, NC—, HO—, andC₁₋₃-alkyl-O—,

-   -   wherein each alkyl group or sub-group within the groups        mentioned under R¹-G2 is optionally substituted with 1 or more F        atoms.

R¹-G3:

According to one embodiment the group R¹ is selected from the groupR¹-G3 consisting of H, F, Cl, H₃C—, H₃C—H₂C—, (H₃C)₂CH—, F₃C—, andH₃C—O—.

R¹-G4:

According to one embodiment the group R¹ is selected from the groupR¹-G4 consisting of H₃C—.

R²:

R²-G1:

The group R² is preferably selected from the group R²-G1 as definedhereinbefore.

R²-G2:

In another embodiment the group R² is selected from the group R²-G2consisting of H, F, Cl, H₃C—, F₃C—, NC—, and H₃CO—.

R²-G3:

In another embodiment the group R² is selected from the group R²-G3consisting of H and F.

R²-G4:

In another embodiment the group R² is selected from the group R²-G4consisting of H.

R²-G5:

In another embodiment the group R² is selected from the group R²-G5consisting of F.

R³:

R³-G1:

The group R³ is preferably selected from the group R³-G1 as definedhereinbefore.

R³-G2:

In another embodiment the group R³ is selected from the group R³-G2consisting of of H, F, Cl, H₃C—, NC—, and H₃CO—.

R³-G3:

In another embodiment the group R³ is selected from the group R³-G3consisting of H.

R^(N):

R^(N)-G1:

The group R^(N) is preferably selected from the group R^(N)-G1 asdefined hereinbefore.

R^(N)-G2:

In another embodiment the group R^(N) is selected from the groupR^(N)-G2 consisting of H, C₁₋₃-alkyl, HO—C₁₋₄-alkyl-H₂C—,H₃C—O—C₁₋₄-alkyl-, C₁₋₃-alkyl-C(═O)—, and C₁₋₃-alkyl-S(═O)₂—.

R^(N)-G3:

In another embodiment the group R^(N) is selected from the groupR^(N)-G3 consisting of H, H₃C—, HO—C₃-alkyl-H₂C—, H₃C—C(═O)—, andH₃C—S(═O)₂—.

m:

m is an integer selected from 1, 2, 3 and 4.

Preferably, m is an integer selected from 1 and 2.

More preferably, m is 2.

n:

n is an integer selected from 1, 2 and 3.

Preferably, n is an integer selected from 1 and 2.

More preferably, n is 1.

The following preferred embodiments of compounds of the formula I aredescribed using generic formulae I.1, I.2, I.3, and I.4, wherein anytautomers, solvates, hydrates and salts thereof, in particular thepharmaceutically acceptable salts thereof, are encompassed.

Examples of preferred subgeneric embodiments (E) according to thepresent invention are set forth in the following table 1, wherein eachsubstituent group of each embodiment is defined according to thedefinitions set forth hereinbefore and wherein all other substituents ofthe formulae I, I.1, I.2, I.3, and I.4 are defined according to thedefinitions set forth hereinbefore. For example, the entry -G1 in thecolumn under R— and in the line of E1 means that in embodiment E1substituent R is selected from the definition designated R-G1. The sameapplies analogously to the other variables incorporated in the generalformulae.

TABLE 1 E R— R¹— R²— R³— R^(N)— m n E1 —G1 —G1 —G1 —G1 —G1 1, 2, 3, 4 1,2, 3 E2 —G1 —G1 —G1 —G2 —G2 1, 2 1, 2 E3 —G1 —G1 —G1 —G3 —G3 1, 2 1, 2E4 —G1 —G1 —G2 —G3 —G3 1, 2 1, 2 E5 —G1 —G2 —G2 —G3 —G1 1, 2 1, 2 E6 —G1—G2 —G2 —G2 —G2 1, 2 1, 2 E7 —G1 —G2 —G2 —G3 —G3 1, 2 1, 2 E8 —G2 —G1—G1 —G1 —G1 1, 2 1, 2 E9 —G3 —G1 —G1 —G1 —G1 1, 2 1, 2 E10 —G3 —G1 —G2—G2 —G2 1, 2 1, 2 E11 —G3 —G2 —G2 —G2 —G2 1, 2 1, 2 E12 —G2 —G2 —G2 —G3—G3 1, 2 1, 2 E13 —G3 —G2 —G2 —G3 —G3 1, 2 1, 2 E14 —G1 —G3 —G2 —G3 —G31, 2 1, 2 E15 —G1 —G2 —G3 —G3 —G3 1, 2 1, 2 E16 —G1 —G3 —G3 —G3 —G3 1, 21, 2 E17 —G1 —G4 —G3 —G3 —G3 1, 2 1, 2 E18 —G2 —G3 —G2 —G3 —G3 1, 2 1, 2E19 —G2 —G2 —G3 —G3 —G3 1, 2 1, 2 E20 —G2 —G3 —G3 —G3 —G3 1, 2 1, 2 E21—G2 —G4 —G3 —G3 —G3 1, 2 1, 2 E22 —G3 —G3 —G2 —G3 —G3 1, 2 1, 2 E23 —G3—G2 —G3 —G3 —G3 1, 2 1, 2 E24 —G3 —G3 —G3 —G3 —G3 1, 2 1, 2 E25 —G3 —G4—G3 —G3 —G3 1, 2 1, 2 E26 —G4 —G3 —G2 —G3 — 2 1, 2 E27 —G4 —G2 —G3 —G3 —2 1 E28 —G4 —G3 —G3 —G3 — 2 1 E29 —G4 —G4 —G3 —G3 — 2 1 E30 —G5 —G3 —G2—G3 — 2 1, 2 E31 —G5 —G2 —G3 —G3 — 2 1 E32 —G5 —G3 —G3 —G3 — 2 1 E33 —G5—G4 —G3 —G3 — 2 1

Another embodiment concerns those compounds of formula I, wherein

R is selected from the group consisting of

H, F, Cl, H₂NC(═O)—, H₃CNH—C(═O)—, (H₃C)₂N—C(═O)—, HOOC—;

C₁₋₃-alkyl optionally substituted with 1 or more F or optionallymonosubstituted with HO—;

cyclopropyl optionally monosubstituted with NC—;

H₃C—O— optionally monosubstituted with C₁₋₄-alkyl, HOOC—, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, or 1,1-dioxotetrahydrothiopyranyl,

-   -   wherein the C₁₋₄-alkyl group optionally attached to H₃C—O— is        optionally monosubstituted with NC—, HO— or H₃C—S(═O)₂—, and    -   wherein said oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and        1,1-dioxotetrahydrothiopyranyl groups are optionally        monosubstituted with H₃C— or HO—;

tetrahydrofuranyl-O— optionally monosubstituted with HO—;tetrahydropyranyl-O—; and

a heteroaryl group selected from pyrazolyl, [1,3,4]oxadiazolyl,tetrazolyl, pyridyl, pyridin-2-onyl, pyrazinyl, pyrimidinyl,pyrimidin-2-onyl, and pyrimidin-4-onyl,

-   -   wherein each of said heteroaryl groups is optionally        monosubstituted with H₃C— or H₃C—O—, and

wherein each H—N group in said heteroaryl groups is optionally replacedwith H₃C—N or (H₃C)₂C(OH)—H₂C—N;

R¹ is H₃C—;

-   -   m is 2;

R² is H or F;

-   -   n is 1; and

R³ is H.

Another embodiment concerns those compounds of formula I, wherein

R is selected from the group consisting of

F, Cl, H₃C—, H₃C—H₂C—, (H₃C)₂CH—,

F₃C—, HOCH₂—, H₂N—C(═O)—, H₃C—NH—C(═O)—, (H₃C)₂N—C(═O)—, HOOC—, H₃C—O—,

wherein the asterisk (-*) indicates the site/point of attachment;

R¹ is H₃C—;

m is 2;

R² is H or F;

n is 1; and

R³ is H.

Another embodiment concerns those compounds of formula I, wherein

R is

wherein the asterisk (-*) indicates the site/point of attachment;

R¹ is H₃C—;

m is 2;

R² is H or F;

n is 1; and

R³ is H.

Particularly preferred compounds, including their tautomers andstereoisomers, the salts thereof, or any solvates or hydrates thereof,are described in the experimental section hereinafter.

The compounds according to the invention and their intermediates may beobtained using methods of synthesis which are known to the one skilledin the art and described in the literature of organic synthesis forexample using methods described in “Comprehensive OrganicTransformations”, 2^(nd) Edition, Richard C. Larock, John Wiley & Sons,2010, and “March's Advanced Organic Chemistry”, 7^(th) Edition, MichaelB. Smith, John Wiley & Sons, 2013. Preferably the compounds are obtainedanalogously to the methods of preparation explained more fullyhereinafter, in particular as described in the experimental section. Insome cases the sequence adopted in carrying out the reaction schemes maybe varied. Variants of these reactions that are known to the skilled manbut are not described in detail here may also be used. The generalprocesses for preparing the compounds according to the invention willbecome apparent to the skilled man on studying the schemes that follow.Starting compounds are commercially available or may be prepared bymethods that are described in the literature or herein, or may beprepared in an analogous or similar manner. Before the reaction iscarried out any corresponding functional groups in the compounds may beprotected using conventional protecting groups. These protecting groupsmay be cleaved again at a suitable stage within the reaction sequenceusing methods familiar to the skilled man and described in theliterature for example in “Protecting Groups”, 3^(rd) Edition, Philip J.Kocienski, Thieme, 2005, and “Protective Groups in Organic Synthesis”,4^(th) Edition, Peter G. M. Wuts, Theodora W. Greene, John Wiley & Sons,2006.

The compounds of the invention I are preferably accessed from aprecursor II that bears the carboxylic acid function in a protected ormasked form as sketched in Scheme 1; R, R¹, R², R³, m and n have themeanings as defined hereinbefore and hereinafter. Suited precursorgroups for the carboxylic acid may be, e.g., a carboxylic ester, acarboxylic amide, cyano, an olefin, an oxazole, or a thiazole. All thesegroups have been transformed into the carboxylic acid function bydifferent means which are described in the organic chemistry literatureand are known to the one skilled in the art. The preferred precursorgroup is a C₁₋₄-alkyl or benzyl carboxylate, each of which may beadditionally mono- or polysubstituted with fluorine, methyl, and/ormethoxy. These ester groups may be hydrolyzed with an acid, such ashydrochloric acid or sulfuric acid, or an alkali metal hydroxide, suchas lithium hydroxide, sodium hydroxide, or potassium hydroxide, to yieldthe carboxylic acid function. The hydrolysis is preferably conducted inaqueous solvents, such as water and tetrahydrofuran, 1,4-dioxane,alcohol, e.g., methanol, ethanol, and isopropanol, or dimethylsulfoxide, at 0 to 120° C. A tert-butyl ester is preferably cleavedunder acidic conditions, e.g., trifluoroacetic acid or hydrochloricacid, in a solvent such as dichloromethane, 1,4-dioxane, isopropanol, orethyl acetate. A benzyl ester is advantageously cleaved using hydrogenin the presence of a transition metal, preferably palladium on carbon.Benzyl esters bearing electron donating groups, such as methoxy, on thearomatic ring may also be removed under oxidative conditions; cericammonium nitrate (CAN) or 2,3-dichloro-5,6-dicyanoquinone (DDQ) are twocommonly used reagents for this approach. The carboxylic acid group mayalso be introduced at an earlier stage of the synthesis, e.g., prior tothe coupling of the pyridine part with the indanylamino residue or theC—C coupling of the two phenyl subgroups as described in theexperimental section.

Compound II, in turn, may be obtained from aminoindane III and pyridineIV which bears the carboxylic acid or a precursor group thereof and aleaving group (Scheme 2); R, R¹, R², R³, m and n in Scheme 2 have themeanings as defined hereinbefore and hereinafter. The leaving group LGin IV may be replaced with the NH group in III via a transition metalcatalyzed coupling reaction. Suited pyridines IV for this approach bearCl, Br, or I as LG, and the preferred catalyst is derived from Cu, Ni,or Pd. The catalyst or the precursor thereof may be a complex of thetransition metal with ligands such as phosphines, e.g.,tri-tert-butylphosphine, tricyclohexylphosphine, optionally substitutedbiphenyl-dicyclohexyl-phosphines, optionally substitutedbiphenyl-di-tert-butylphosphines, Xantphos,1,1′-bis(diphenylphosphino)ferrocene, triphenylphosphine,tritolylphosphine, or trifurylphosphine, phosphites, 1,3-disubstitutedimidazole carbenes, 1,3-disubstituted imidazolidine carbenes,oxalamides, dibenzylideneacetone, allyl, or nitriles, an elemental formof the transition metal such as palladium on carbon or nanoparticles ofpalladium, or a salt of the transition metal such as fluoride, chloride,bromide, acetate, triflate, acetylacetonate, or trifluoroacetate thatmay be combined with a separately added ligand. The reaction ispreferably conducted in the presence of a base such as an alcoholate,e.g., LiOtBu, NaOtBu, KOtBu, and KOtPent, a hydroxide, e.g., LiOH, NaOH,and KOH, lithium hexamethyldisilazide, K₃PO₄, a carbonate such asCs₂CO₃, or phenolate such as sodium2,6-di-tert-butyl-4-methyl-phenolate. Additives, such as silver salts,e.g., AgNO₃, AgOSO₂CF₃, and Ag₂CO₃, may be beneficial or essential forsome of the reactions to proceed. The coupling reactions are preferablyconducted in benzene, toluene, tetrahydrofuran, 1,2-dimethoxyethane,1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidinone, dimethyl sulfoxide, alcohol such as tBuOH ortPentOH, water, or mixtures thereof, at temperatures in the range of 20to 180° C. For employing the bromo-pyridine IV (LG=Br) particularlysuited reaction conditions includechloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II)as catalyst precursor and sodium tert-butoxide or sodium tert-pentoxideas base, in 1,4-dioxane or toluene at 60 to 110° C.; optionally, anadditional equivalent of2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenylis added. The bromo-pyridine IV (LG=Br) and the indanylamine III arealso advantageously coupled with CuI and an oxalamide, e.g.,2-(2,6-dimethylphenylamino)-2-oxoacetic acid, in the presence of a base,e.g., K₃PO₄, in dimethylsulfoxide at 60 to 110° C.

Intermediate III is conveniently obtained from indanol V which, in turn,may be prepared from indanone VI or VI′ (Scheme 3); R, R¹, R², m and nin Scheme 3 have the meanings as defined hereinbefore and hereinafter.

The reduction of the keto group in compound VI or VI′ is a standardtransformation in organic synthesis which may be accomplished withlithium borohydride, sodium borohydride, lithium aluminum hydride, ordiisobutylaluminum hydride. While sodium borohydride is commonlyemployed in aqueous or alcoholic solution at 0 to 60° C., the otherreducing agents mentioned are preferably used in inert solvents, such astetrahydrofuran, diethyl ether, dichloromethane, and toluene, at −80 to60° C. The reduction of the keto group may also be conducted in astereoselective fashion providing the alcohol in enantiomericallyenriched or pure form. Suited chiral reducing agents are boranescombined with an enantiomerically pure [1,3,2]oxazaborol(Corey-Bakshi-Shibata reduction or Corey-Itsuno reduction) or formicacid, formates, hydrogen, or silanes in the presence of anenantiomerically pure transition metal catalyst. Typical reactionconditions for the former approach comprise a borane, e.g., boranedimethyl sulfide complex, and (R)- or(S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborolin, e.g., dichloromethane, toluene, methanol, tetrahydrofuran, ormixtures thereof, at −10 to 60° C. Employing a chiral transition metalcatalyst, such as a ruthenium complex, e.g.,chloro{[(1S,2S)-(−)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)-amido}-mesitylene)ruthenium(II),may deliver the hydroxy compound with high enantiomeric excess using ahydride source, e.g., formic acid, in the presence of a base, e.g.,triethylamine, in dichloromethane, at −20 to 60° C.

The OH group in compound V may be replaced with NH₂ following a two-stepprocedure via a protected, e.g., as phthalimide, or masked, e.g., asazide, amino derivative. Phthalimide can be introduced employing theconditions of the Mitsunobu reaction. The transformation is routinelyconducted with phthalimide, a phosphine, and an azodicarboxylic ester oramide in tetrahydrofuran, 1,4-dioxane, diethyl ether, toluene, benzene,dichloromethane, or mixtures thereof, at −30 to 100° C. Phosphinescommonly used are triphenylphosphine and tributylphosphine which areregularly combined with dimethyl azodicarboxylate, diethylazodicarboxylate, diisopropyl azodicarboxylate, di-(4-chlorobenzyl)azodicarboxylate, dibenzyl azodicarboxylate, di-tert-butylazodicarboxylate, azodicarboxylic acid bis-(dimethylamide),azodicarboxylic acid dipiperidide, or azodicarboxylic acid dimorpholide.The amino group may be liberated from phthalimide using hydrazine inethanol, ethylene-1,2-diamine in n-butanol, or 1-butylamine inn-butanol.

The azide group can be introduced from the hydroxy precursors V and V′employing hydrazoic acid or phosphoryl azide and the conditions of theMitsunobu reaction as described above or variants thereof. Phosphorylazide combined with a base, such as 1,8-diazabicyclo[5.4.0]undecene, mayalso accomplish the transformation in tetrahydrofuran or toluene at −10to 80° C. The azide is transformed into the amino function using, e.g.,hydrogen in the presence of a transition metal such as palladium oncarbon.

Both proceedings may give the aminoindane III in enantiomerically pureform when starting from the isomerically pure precursor V or V′.

The phenyl residue on indane III is attached via a transition metalcatalyzed coupling reaction that can be carried out at various stages ofthe synthesis sequence as depicted in Scheme 3 and the experimentalsection. The transition metal catalyst is preferably derived frompalladium, nickel, copper, or iron, more preferably palladium. Theactive catalyst may be a complex of the transition metal with ligandssuch as phosphines, e.g. tri-tert-butylphosphine,tricyclohexylphosphine, optionally substitutedbiphenyl-dicyclohexyl-phosphines, optionally substitutedbiphenyl-di-tert-butyl-phosphines,1,1′-bis(diphenylphosphino)-ferrocene, triphenylphosphine,tritolylphosphine, or trifurylphosphine, phosphites, 1,3-disubstitutedimdiazole carbenes, 1,3-disubstituted imidazolidine carbenes,dibenzylideneacetone, allyl, or nitriles, an elemental form of thetransition metal, such as palladium on carbon or nanoparticles of ironor palladium, or a salt such as fluoride, chloride, bromide, acetate,triflate, or trifluoroacetate. The phenyl group is preferably employedas boronic acid or ester, trifluoroborate, or zinc halide, thenucleophilic reaction partner (VI″), and the indane derivative aschloride, bromide or iodide, the electrophilic reaction partner (III′,V′, or VI″). Depending on the nucleophiles the reactions are preferablyconducted in benzene, toluene, ether, tetrahydrofuran,1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide,alcohol, water, or mixtures thereof, at 0 to 160° C. Reactions employingboronic acids or esters or trifluoroborates are commonly conducted inthe presence of a base such as an alcoholate, a hydroxide, e.g., LiOH,NaOH, and KOH, K₃PO₄, a carbonate, e.g., Li₂CO₃, Na₂CO₃, K₂CO₃, andCs₂CO₃, an amine, or a fluoride, e.g., KF. Additives such as halidesalts, e.g., lithium chloride, silver salts, e.g., silver oxide andtriflate, and/or copper salts, e.g., copper chloride and copperthiophene-2-carboxylate, may be beneficial or even essential for thereaction to proceed. The reactivities of the reaction partners (reactingcarbons) described may be reversed, i.e. the phenyl derivative is theelectrophilic and the indanyl derivative the nucleophilic reactionpartner, providing the same products under the same or similarconditions.

Compounds of general structure IV wherein R³ has the meaning as definedhereinbefore and hereinafter and CP is a suitable carboxylic acid estergroup can be synthesized as summarized in Scheme 4.

Acrylic acid ester VII is reacted with a methylene synthetic equivalentto give ester IV′. Suitable reagents for this transformation includediazomethane in the presence of a transition metal catalyst such aspalladium diacetate (see, e.g., WO2011/94890), trimethyloxosulfoniumhalide in the presence of a base such as sodium hydride (see, e.g.,WO2005/103032), and diiodomethane in the presence of copper and zinc(see, e.g., US628476). Generally, use of a trans-acrylic acid ester inthese reactions leads to predominant formation of a trans-substitutedcyclopropyl ester. Enantioselective variants of this type of reactionare reported in the literature such as the one using diazomethane andchiral copper complexes (see, e.g., Tetrahedron Asymmetry 2003, 14,867-872).

The pyridine IV′ is also obtained from vinylpyridine VIII anddiazoacetic ester IX in the presence of a transition metal catalyst.Suitable catalyst systems for this transformation include, for example,palladium diacetate (see, e.g., WO2007/104717), cobalt(II) porphyrins(see, e.g., WO2006/103503), rhodium complexes (see, e.g., WO2006/87169),and copper complexes (see, e.g., WO2010/51819). Mixtures of cis- andtrans-cyclopropyl esters are generally formed with the trans-systempredominant and the ratio depending on the catalyst system andsubstrates used. Enantioselective reactions of this type are reportedusing chiral transition metal catalysts derived from copper and cobalt(see, e.g., J. Am. Chem Soc. 1991, 113, 726-728) and variations thereof.

Another proceeding to access compound IV′ employs epoxide X andphosphonoacetate XI. The reaction is commonly carried out in thepresence of a base such as an alcoholate, e.g., NaOEt, NaOtBu, NaOtPent,KOtBu, and KOtPent, LiN(iPr)₂, LiN(SiMe₃)₂, NaH, or nBuLi, in a solventsuch as hexane, benzene, toluene, tetrahydrofuran, 1,2-dimethoxyethane,1,4-dioxane, dimethylsulfoxide, or mixtures thereof, at 0 to 160° C. Theepoxide X is accessed using standard procedures in organic synthesissuch as epoxidation of the corresponding alkene, base inducedcyclization of the corresponding chloro- or bromohydrin derivative, orCorey-Chaykovsky reaction of the corresponding pyridinecarbaldehyde andan appropriate sulfur ylide.

The synthetic routes presented may rely on the use of protecting groups.For example, potentially reactive groups present, such as hydroxy,carbonyl, carboxy, amino, alkylamino, or imino, may be protected duringthe reaction by conventional protecting groups which are cleaved againafter the reaction. Suitable protecting groups for the respectivefunctionalities and their removal are well known to the one skilled inthe art and are described in the literature of organic synthesis forexample in “Protecting Groups”, 3^(rd) Edition, Philip J. Kocienski,Thieme, 2005, and “Protective Groups in Organic Synthesis”, 4^(th)Edition, Peter G. M. Wuts, Theodora W. Greene, John Wiley & Sons, 2006.

The compounds of general formula I may be resolved into theirenantiomers and/or diastereomers as mentioned below. Thus, for example,cis/trans mixtures may be resolved into their cis and trans isomers andracemic compounds may be separated into their enantiomers.

The cis/trans mixtures may be resolved, for example, by chromatographyinto the cis and trans isomers thereof. The compounds of general formulaI which occur as racemates may be separated by methods known per se intotheir optical antipodes and diastereomeric mixtures of compounds ofgeneral formula I may be resolved into their diastereomers by takingadvantage of their different physico-chemical properties using methodsknown per se, e.g. chromatography and/or fractional crystallization; ifthe compounds obtained thereafter are racemates, they may be resolvedinto the enantiomers as mentioned below.

The racemates are preferably resolved by column chromatography on chiralphases or by crystallization from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as esters or amides with the racemic compound. Saltsmay be formed with enantiomerically pure acids for basic compounds andwith enantiomerically pure bases for acidic compounds.

Diastereomeric derivatives are formed with enantiomerically pureauxiliary compounds, e.g. acids, their activated derivatives, oralcohols. Separation of the diastereomeric mixture of salts orderivatives thus obtained may be achieved by taking advantage of theirdifferent physico-chemical properties, e.g. differences in solubility;the free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acidscommonly used for such a purpose as well as optically active alcoholsapplicable as auxiliary residues are known to those skilled in the art.

As mentioned above, the compounds of formula I may be converted intosalts, particularly for pharmaceutical use into the pharmaceuticallyacceptable salts. As used herein, “pharmaceutically acceptable salts”refer to derivatives of the disclosed compounds wherein the parentcompound is modified by making acid or base salts thereof.

The compounds according to the invention are advantageously alsoobtainable using the methods described in the examples that follow,which may also be combined for this purpose with methods known to theskilled man from the literature.

Terms and Definitions

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

The terms “compound(s) according to this invention”, “compound(s) offormula (I)”, “compound(s) of the invention” and the like denote thecompounds of the formula (I) according to the present inventionincluding their tautomers, stereoisomers and mixtures thereof and thesalts thereof, in particular the pharmaceutically acceptable saltsthereof, and the solvates and hydrates of such compounds, including thesolvates and hydrates of such tautomers, stereoisomers and saltsthereof.

The terms “treatment” and “treating” embrace both preventative, i.e.prophylactic, or therapeutic, i.e. curative and/or palliative,treatment. Thus the terms “treatment” and “treating” comprisetherapeutic treatment of patients having already developed saidcondition, in particular in manifest form. Therapeutic treatment may besymptomatic treatment in order to relieve the symptoms of the specificindication or causal treatment in order to reverse or partially reversethe conditions of the indication or to stop or slow down progression ofthe disease. Thus the compositions and methods of the present inventionmay be used for instance as therapeutic treatment over a period of timeas well as for chronic therapy. In addition the terms “treatment” and“treating” comprise prophylactic treatment, i.e. a treatment of patientsat risk to develop a condition mentioned hereinbefore, thus reducingsaid risk.

When this invention refers to patients requiring treatment, it relatesprimarily to treatment in mammals, in particular humans.

The term “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease or condition, (ii) attenuates, ameliorates, oreliminates one or more symptoms of the particular disease or condition,or (iii) prevents or delays the onset of one or more symptoms of theparticular disease or condition described herein.

The terms “modulated” or “modulating”, or “modulate(s)”, as used herein,unless otherwise indicated, refer to the activation of theG-protein-coupled receptor GPR40 with one or more compounds of thepresent invention.

The terms “mediated” or “mediating” or “mediate”, as used herein, unlessotherwise indicated, refer to the (i) treatment, including prevention ofthe particular disease or condition, (ii) attenuation, amelioration, orelimination of one or more symptoms of the particular disease orcondition, or (iii) prevention or delay of the onset of one or moresymptoms of the particular disease or condition described herein.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom, radical or moiety is replaced with aselection from the indicated group, provided that the atom's normalvalence is not exceeded, and that the substitution results in anacceptably stable compound.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In general,for groups comprising two or more subgroups, the last named subgroup isthe radical attachment point, for example, the substituent“aryl-C₁₋₃-alkyl-” means an aryl group which is bound to aC₁₋₃-alkyl-group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail.

An asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

The numeration of the atoms of a substituent starts with the atom whichis closest to the core or to the group to which the substituent isattached.

For example, the term “3-carboxypropyl-group” represents the followingsubstituent:

wherein the carboxy group is attached to the third carbon atom of thepropyl group.

The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or“cyclopropylmethyl-” group represent the following groups:

The asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

In a definition of a group the term “wherein each X, Y and Z group isoptionally substituted with” and the like denotes that each group X,each group Y and each group Z either each as a separate group or each aspart of a composed group may be substituted as defined. For example adefinition “R^(ex) denotes H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyl or C₁₋₃-alkyl-O—, wherein each alkyl group isoptionally substituted with one or more L^(ex).” or the like means thatin each of the beforementioned groups which comprise the term alkyl,i.e. in each of the groups C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl andC₁₋₃-alkyl-O—, the alkyl moiety may be substituted with L^(ex) asdefined.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc. . . . ) and racematesthereof as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist, as well assalts, including pharmaceutically acceptable salts thereof and solvatesthereof such as for instance hydrates including solvates of the freecompounds or solvates of a salt of the compound.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts) also comprise a part of the invention.

The term halogen generally denotes fluorine, chlorine, bromine andiodine.

The term “C_(1-n)-alkyl”, wherein n is an integer from 1 to n, eitheralone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atoms.For example the term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(1-n)-alkylene” wherein n is an integer 1 to n, either aloneor in combination with another radical, denotes an acyclic, straight orbranched chain divalent alkyl radical containing from 1 to n carbonatoms. For example the term C₁₋₄-alkylene includes —(CH₂)—, —(CH₂—CH₂)—,—(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—,—(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—,—(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—,—(CH₂—C(CH₃)₂)—, —(C(CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—,—(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—,—(CHCH(CH₃)₂)— and —C(CH₃)(CH₂CH₃)—.

The term “C_(2-n)-alkenyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenyl includes —CH═CH₂,—CH═CH—CH₃, —CH₂—CH═CH₂.

The term “C_(2-n)-alkynyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynyl includes —C≡CH,—C≡C—CH₃, —CH₂—C≡CH.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer 4 to n, eitheralone or in combination with another radical denotes a cyclic,saturated, unbranched hydrocarbon radical with 3 to n C atoms. Thecyclic group may be mono-, bi-, tri- or spirocyclic, most preferablymonocyclic. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclododecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl,norpinyl, norbonyl, norcaryl, adamantyl, etc.

Many of the terms given above may be used repeatedly in the definitionof a formula or group and in each case have one of the meanings givenabove, independently of one another.

Pharmacological Activity

The activity of the compounds of the invention may be demonstrated usingthe following assay:

IP₁ accumulation measurements using the IPOne assay system—1321N1 cellsstably expressing human GPR40 receptor (Euroscreen, Belgium) are seeded24 h before the assay in white 384-well plates in culture mediumcontaining 10% FCS, 1% Na-Pyruvate and 400 μg/mL G418. IP₁ is assayedaccording to the manufacturer's description (Cisbio Bioassays, France).In brief, the assay is started by substitution of the culture medium bystimulation buffer (Hepes 10 mM, CaCl₂ 1 mM, MgCl₂ 0.5 mM, KCl 4.2 mM,NaCl 146 mM, glucose 5.5 mM and LiCl 50 mM, pH 7.4). Cells arestimulated for 1 h at 37° C., 5% CO₂ by addition of the compounds thatare diluted in stimulation buffer containing LiCl. Assays are stopped byadding HTRF-conjugates (IP1-d2 and Anti-IP1 cryptate Tb) and lysisbuffer, provided by the manufacturer. After an incubation time of 1 h atroom temperature plates are measured using an EnVision™, Perkin Elmer.The obtained fluorescence ratios at 665/615 nM are then used tocalculate the pEC₅₀ values using Assay Explorer 3.3 Software (Accelrys,Inc.) by interpolation using an IP₁ reference curve and subsequentsigmoidal curve fitting allowing for a variable hill slope.

The compounds according to the invention typically have EC₅₀ values inthe range from about 1 nM to about 10 μM, preferably less than 1 μM,more preferably less than 100 nM.

EC₅₀ values for compounds according to the invention are shown in thefollowing table. The number of the compound corresponds to the number ofthe Example in the experimental section.

TABLE 2 Exam- EC₅₀ Exam- EC₅₀ Exam- EC₅₀ Exam- EC₅₀ ple [nM] ple [nM]ple [nM] ple [nM] 1 11 2 4 3 107 4 7 5 35 6 3 7 5 8 100 9 24 10 146 1130 12 10 13 25 14 4 15 8 16 924 17 10 18 5 19 12 20 2 21 2 22 5 23 66824 4 25 344 26 6 27 148 28 5 29 4 30 3 31 27 32 7 33 12 34 10 35 11 3615 37 19 38 18 39 148

Chemical Stability

Degradation kinetics is used to simulate chemical stability of compoundsin the acidic part of the gastro intestinal tract. The compounds of theinvention show superior chemical stability in acidic aqueous media (pHvalue ca. 1.2) compared to the bulk of compounds explicitly disclosed inWO 2013/178575. Their application as medical drugs to treat humandiseases is therefore less restricted and troublesome.

The chemical stability of the compounds of the invention at pH value ofca. 1.2 is determined as follows:

Compound is dissolved in an HPLC vial either in a mixture ofacetonitrile/0.1 M aqueous HCl (2:3; pH ca. 1.2) or in a mixture ofacetonitrile/McIlvaine buffer pH 7.4 (2:3) to get a concentration ofapproximately 0.25 mg/ml. The vial was then transferred into an HPLCautosampler system and maintained at a temperature of 37° C. A firstsample is taken and injected immediately into a standard HPLC systemwith a UV DAD detector. Further samples are injected after 2, 4, 6, 8and 10 hours. Amount of degraded compound is measured by determining therecovery rate of compound [%] for each injection using an HPLC standardgradient method. Therefore the peak area of the main peak for the firstinjection (AU_(t0)) is determined and set as 100%. Peak area of the mainpeak is determined also for the further injections(AU_(tn, n=2, 4, 6, 8, 10)) and expressed as fraction of(AU_(t0))/(AU_(tn, n=2, 4, 6, 8, 10)) [%].

The amount of degraded compound according to the invention after 2 h atpH value of ca. 1.2 determined as described above is typicallysignificantly below 1.5%, mostly below 0.5%.

The following table compares the amount of degradation after 2 h at pHvalue of ca. 1.2 of compounds according to the invention and compoundsfrom WO 2013/178575 (for structures see below Table 3).

TABLE 3 Amount of Amount of Example in this degradation Example indegradation invention after 2 h WO 2013/178575 after 2 h 2 <0.5% 17 8% 4<0.5% 11 5% 5 <0.5% 15 3% 28 <0.5% 33 8% 54 2.5% 

Chemical structures of the examples from case WO 2013/178575 listed inthe tables 3 to 6:

Solubility

The aqueous solubility of the compounds of the invention is determinedby comparing the amount dissolved in buffer to the amount in anacetonitrile/water (1/1) solution. Starting from a 10 mM DMSO stocksolution aliquots are diluted with acetonitrile/water (1/1) or buffer,respectively. After 24 h of shaking, the solutions are filtrated andanalyzed by LC-UV. The amount dissolved in buffer is compared to theamount in the acetonitrile solution.

Solubility is usually being measured from 0.001 to 0.125 mg/mL at a DMSOconcentration of 2.5%. If more than 90% of the compound is dissolved inbuffer, the value is marked with “>”.

The compounds of the invention show higher solubility at low pH value(pH 2.2, emulating the acidic part of the gastro intestinal tract)compared with the bulk of compounds explicitly disclosed in WO2013/178575. Their development and application is therefore moreconvenient and reliable. The following table presents the data forselected compounds of this invention and compounds from WO 2013/178575(for structures see above below Table 3).

TABLE 4 Solubility at pH Solubility at pH Example in this value 2.2Example in value 2.2 invention [μg/mL] WO 2013/178575 [μg/mL] 2 100 17<1 30 99 45 <1 4 97 15 <1 5 121 54 <1 6 68 7 84 8 62 9 <1 11 >120 12 10513 105 14 110 15 120 16 96 17 64 18 >130 19 95 20 113 21 91 22 106 23 9724 >122 25 110 26 90 27 112 28 111 29 117 31 87 32 123 33 103 34 111 35106 36 91 37 119 38 >154 39 118

Inhibition of CYP-2C8

The inhibition of cytochrome P450 2C8-isoenzyme catalyzed deethylationof amodiaquine by the test compound is assayed at 37° C. with humanliver microsomes. All assays are carried out on a robotic system in 96well plates. The final incubation volume contains TRIS buffer (0.1 M),MgCl₂ (5 mM), human liver microsomes (0.05 mg/mL), amodiaquine (1 μM)and the test compound at five different concentrations or no compound(high control) in duplicate (e.g. highest concentration 10-50 μM withsubsequent serial 1:4 dilutions). Following a short preincubationperiod, reactions are started with the cofactor (NADPH, 1 mM) andstopped by cooling the incubation down to 8° C. and subsequently byaddition of one volume of acetonitrile. An internal standardsolution—the stable isotope d5-desethylamodiaquine—is added afterquenching of incubations. Peak area analyte (=metabolite formed) andinternal standard is determined by LC-MS/MS. The resulting peak arearatio analyte to internal standard in these incubations is compared to acontrol activity containing no test compound. Within each of the assayruns, the IC₅₀ of a positive control inhibitor (Montelukast) isdetermined. Experimental IC₅₀ values are calculated by least squareregression according to the following equation:% control activity=(100% control activity/(1+(I/IC ₅₀)S))−Bwith I=inhibitor concentration; S=slope factor; B=background activity(lower plateau of the inhibition curve)

If the inhibition of the reaction is already >50% at the lowestconcentration of the test compound, the IC₅₀ is assigned “<lowestconcentration tested” (usually <0.4 μM). If the inhibition of thereaction is still <50% at the highest concentration of the testcompound, the IC₅₀ is assigned “>highest concentration tested”(usually >50 μM).

The compounds of the invention show lower inhibition of the cytochromeP450 2C8-isoenzyme compared with the bulk of compounds explicitlydisclosed in WO 2013/178575. Their potential for causing unwantedside-effects is therefore decreased. The following table displays thedata for selected compounds of this invention and compounds from WO2013/178575 (for structures see above below Table 3).

TABLE 5 Example in this IC₅₀ Example in IC₅₀ invention [μM] WO2013/178575 [μM] 2 20 17 6 4 >50 11 12 30 20 45 5 5 >50 15 10 6 29 33 57 >50 54 9 8 >50 9 20 11 >50 12 30 13 40 14 19 15 32 16 >50 17 19 18 2119 7 20 34 21 15 22 8 23 43 24 11 25 49 26 14 27 >50 28 40 29 14 31 1532 26 33 40 34 45 35 31 36 10 37 41 38 >50 39 >50

Inhibition of CYP-2C9

The inhibition of cytochrome P450 2C9-isoenzyme catalyzed hydroxylationof diclofenac by the test compound is assayed at 37° C. with human livermicrosomes. All assays are carried out on a robotic system in 96 wellplates. The final incubation volume contains TRIS buffer (0.1 M), MgCl₂(5 mM), human liver microsomes (0.1 mg/mL), diclofenac (10 μM) and thetest compound at five different concentrations or no compound (highcontrol) in duplicate (e.g., highest concentration 10-50 μM withsubsequent serial 1:4 dilutions). Following a short preincubationperiod, reactions are started with the cofactor (NADPH, 1 mM) andstopped by cooling the incubation down to 8° C. and subsequently byaddition of one volume of acetonitrile. An internal standardsolution—the stable isotope ¹³C6-hydroxydiclofenac—is added afterquenching of incubations. Peak area analyte (=metabolite formed) andinternal standard is determined by LC-MS/MS. The resulting peak arearatio analyte to internal standard in these incubations is compared to acontrol activity containing no test compound. Within each of the assayruns, the IC₅₀ of a positive control inhibitor (sulfaphenazole) isdetermined. Experimental IC₅₀ values are calculated by least squareregression according to the following equation:% control activity=(100% control activity/(1+(I/IC ₅₀)S))−Bwith I=inhibitor concentration; S=slope factor; B=background activity(lower plateau of the inhibition curve)

If the inhibition of the reaction is already >50% at the lowestconcentration of the test compound, the IC₅₀ is assigned “<lowestconcentration tested” (usually <0.4 μM). If the inhibition of thereaction is still <50% at the highest concentration of the testcompound, the IC₅₀ is assigned “>highest concentration tested”(usually >50 μM).

The compounds of the invention show lower inhibition of the cytochromeP450 2C9-isoenzyme compared with the bulk of compounds explicitlydisclosed in WO 2013/178575. Their potential for causing unwantedside-effects is therefore decreased. The following table displays thedata for selected compounds of this invention and compounds from WO2013/178575 (for structures see above below Table 3).

TABLE 6 Example in this IC₅₀ Example in IC₅₀ invention [μM] WO2013/178575 [μM] 2 >50 17 14 4 >50 11 17 30 >50 45 10 5 >50 15 31 6 >5033 7 7 >50 54 10 8 >50 9 >50 11 >50 12 >50 13 >50 14 47 15 >50 16 >50 1736 18 >50 19 26 20 >50 21 36 22 19 23 >50 24 22 25 40 26 16 27 >5028 >50 29 >50 31 31 32 >50 33 >50 34 >50 35 >50 36 22 37 >50 38 >50 39>50

The following compilation showcases the superiority of the compounds ofthis invention over the compounds from WO2013/178575 by head-to-headcomparison of their direct analogs.

Example 2 in this invention

GPR40: IC₅₀ = 4 nM Chemical stability at pH 1.2: <0.5% Solubility (pH2.2) = 100 μg/mL Cyp 2C8: IC₅₀ = 20 μM Cyp 2C9: IC₅₀ > 50 μM Example 4in this invention

GPR40: IC₅₀ = 7 nM Chemical stability at pH 1.2: <0.5% Solubility (pH2.2) = 97 μg/mL Cyp 2C8: IC₅₀ > 50 μM Cyp 2C9: IC₅₀ > 50 μM Example 30in this invention

GPR40: IC₅₀ = 3 nM Solubility (pH 2.2) = 99 μg/mL Cyp 2C8: IC₅₀ = 20 μMCyp 2C9: IC₅₀ > 50 μM Example 17 in WO 2013/178575

IC₅₀ = 4 nM 8% degradation after 2 h at 37° C. < 1 μg/mL IC₅₀ = 6 μMIC₅₀ = 14 μM Example 11 in WO 2013/178575

IC₅₀ = 8 nM 5% degradation after 2 h at 37° C. not determined IC₅₀ = 12μM IC₅₀ = 17 μM Example 45 in WO 2013/178575

IC₅₀ = 8 nM < 1 μg/mL IC₅₀ = 5 μM IC₅₀ = 10 μM

Inhibition of HCN4

In addition, the compounds of the invention show superiority over potentGPR40 agonists of isomeric aminopyridine structure with regard toundesired inhibitory activity on the ion channel HCN4 (potassium/sodiumhyperpolarization-activated cyclic nucleotide-gated channel 4).

HCN4 Assay Procedure

Compound Preparation:

Compounds in solid form were prepared in DMSO at 300× the final assayconcentrations of 10, 3, 1, and 0.3 μM. All 300×DMSO stock solutionswere transferred to a master plate and into assay plates where 2 μl perwell of each 300× solution were placed. All assay plates were stored at−80° C. until the day of assay.

On the day of the assay, the appropriate assay plate was thawed at roomtemperature, centrifuged, and 198 μL of external solution was added andmixed thoroughly. This provided a 1:100 dilution. A further 1:3 dilutionoccurred upon addition to the cells in the IonWorks platform, giving a1:300 dilution in total.

On each assay plate, at least 8 wells were reserved for vehicle control(0.3% DMSO) and at least 8 wells for each positive control. The positivecontrols were tested at a maximal blocking and an approximate IC₅₀concentration. The positive control compounds are outlined below.

Ion channel positive control and concentrations:

50 μM and 3 mM Cesium Chloride.

Electrophysiological Recording Solutions:

External solution:

Na Gluconate 104 mM NaCl 10 mM KCl 30 mM MgCl2 1 mM CaCl2 1.8 mM HEPES10 mM Glucose 5 mMmM

pH 7.3 (titrated with 10M NaOH)

Internal solution:

K Gluconate 130 mM NaCl 10 mM MgCl2 1 mM HEPES 10 mM EGTA 1 mM

pH 7.3 (titrated with 10M KOH)

Amphotericin B was used to obtain electrical access to the cell interiorat a final concentration of 200 μg/ml in internal recording solution.

Experimental Protocols and Data Analysis:

Human HCN4 currents were evoked by a single pulse from a holdingpotential of −30 mV to a potential of −110 mV for a duration of fourseconds prior to returning to −30 mV. The voltage protocol was applied(Pre), compounds added, incubated for 600 seconds, and the voltageprotocol was applied a final time (Post) on the IonWorks Quattro.

The parameter measured was the maximum inward current evoked uponstepping to −110 mV from the holding potential of −30 mV. All data werefiltered for seal quality, seal drop, and current amplitude. The maximumcurrent amplitude of the single hyperpolarizing pulse was calculatedbefore (Pre) and after (Post) compound addition and the amount of blockassessed by dividing the Post-compound current amplitude by thePre-compound current amplitude.

Selection Criteria for Valid Recordings:

Data Filter Criteria Seal Quality >30 MΩ Seal Drop <50% Seal Drop (SealPre- Compound/Seal Post Compound) Current Amplitude >200 pA

In view of their ability to modulate the activity of theG-protein-coupled receptor GPR40, in particular an agonistic activity,the compounds of general formula I according to the invention, includingthe corresponding salts thereof, are theoretically suitable for thetreatment of all those diseases or conditions which may be affected orwhich are mediated by the activation of the G-protein-coupled receptorGPR40.

Accordingly, the present invention relates to a compound of generalformula I as a medicament.

Furthermore, the present invention relates to the use of a compound ofgeneral formula I or a pharmaceutical composition according to thisinvention for the treatment and/or prevention of diseases or conditionswhich are mediated by the activation of the G-protein-coupled receptorGPR40 in a patient, preferably in a human.

In yet another aspect the present invention relates to a method fortreating a disease or condition mediated by the activation of theG-protein-coupled receptor GPR40 in a mammal that includes the step ofadministering to a patient, preferably a human, in need of suchtreatment a therapeutically effective amount of a compound or apharmaceutical composition of the present invention.

Diseases and conditions mediated by agonists of the G-protein-coupledreceptor GPR40 embrace metabolic diseases or conditions. According toone aspect the compounds and pharmaceutical compositions of the presentinvention are particularly suitable for treating diabetes mellitus, inparticular Type 2 diabetes, Type 1 diabetes, complications of diabetes(such as e.g. retinopathy, nephropathy or neuropathies, diabetic foot,ulcers or macroangiopathies), metabolic acidosis or ketosis, reactivehypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulinresistance, metabolic syndrome, dyslipidaemias of different origins,atherosclerosis and related diseases, obesity, high blood pressure,chronic heart failure, oedema and hyperuricaemia.

The compounds and pharmaceutical compositions of the present inventionare also suitable for preventing beta-cell degeneration such as e.g.apoptosis or necrosis of pancreatic beta cells. The compounds andpharmaceutical compositions of the present invention are also suitablefor improving or restoring the functionality of pancreatic cells, andalso for increasing the number and size of pancreatic beta cells.

Therefore according to another aspect the invention relates to compoundsof formula I and pharmaceutical compositions according to the inventionfor use in preventing, delaying, slowing the progression of and/ortreating metabolic diseases, particularly in improving the glycaemiccontrol and/or beta cell function in the patient.

In another aspect the invention relates to compounds of formula I andpharmaceutical compositions according to the invention for use inpreventing, delaying, slowing the progression of and/or treating type 2diabetes, overweight, obesity, complications of diabetes and associatedpathological conditions.

In addition the compounds and pharmaceutical compositions according tothe invention are suitable for use in one or more of the followingtherapeutic processes:

-   -   for preventing, delaying, slowing the progression of or treating        metabolic diseases, such as for example type 1 diabetes, type 2        diabetes, insufficient glucose tolerance, insulin resistance,        hyperglycaemia, hyperlipidaemia, hypercholesterolaemia,        dyslipidaemia, syndrome X, metabolic syndrome, obesity, high        blood pressure, chronic systemic inflammation, retinopathy,        neuropathy, nephropathy, atherosclerosis, endothelial        dysfunction or bone-related diseases (such as osteoporosis,        rheumatoid arthritis or osteoarthritis);    -   for improving glycaemic control and/or reducing fasting plasma        glucose, postprandial plasma glucose and/or the glycosylated        haemoglobin HbA1C;    -   for preventing, delaying, slowing or reversing the progression        of disrupted glucose tolerance, insulin resistance and/or        metabolic syndrome to type 2 diabetes;    -   for preventing, delaying, slowing the progression of or treating        a condition or a disease selected from among the complications        of diabetes, such as for example retinopathy, nephropathy or        neuropathies, diabetic foot, ulcers or macroangiopathies;    -   for reducing weight or preventing weight gain or assisting        weight loss;    -   for preventing or treating the degradation of pancreatic beta        cells and/or improving and/or restoring the functionality of        pancreatic beta cells and/or restoring the functionality of        pancreatic insulin secretion;    -   for maintaining and/or improving insulin sensitivity and/or        preventing or treating hyperinsulinaemia and/or insulin        resistance.

In particular, the compounds and pharmaceutical compositions accordingto the invention are suitable for the treatment of obesity, diabetes(comprising type 1 and type 2 diabetes, preferably type 2 diabetesmellitus) and/or complications of diabetes (such as for exampleretinopathy, nephropathy or neuropathies, diabetic foot, ulcers ormacroangiopathies).

The compounds according to the invention are most particularly suitablefor treating type 2 diabetes mellitus.

The dose range of the compounds of general formula I applicable per dayis usually from 0.001 to 10 mg per kg body weight, for example from 0.01to 8 mg per kg body weight of the patient. Each dosage unit mayconveniently contain from 0.1 to 1000 mg, for example 0.5 to 500 mg.

The actual therapeutically effective amount or therapeutic dosage willof course depend on factors known by those skilled in the art such asage and weight of the patient, route of administration and severity ofdisease. In any case the compound or composition will be administered atdosages and in a manner which allows a therapeutically effective amountto be delivered based upon patient's unique condition.

The compounds, compositions, including any combinations with one or moreadditional therapeutic agents, according to the invention may beadministered by oral, transdermal, inhalative, parenteral or sublingualroute. Of the possible methods of administration, oral or intravenousadministration is preferred.

Pharmaceutical Compositions

Suitable preparations for administering the compounds of formula I,optionally in combination with one or more further therapeutic agents,will be apparent to those with ordinary skill in the art and include forexample tablets, pills, capsules, suppositories, lozenges, troches,solutions, syrups, elixirs, sachets, injectables, inhalatives andpowders etc. Oral formulations, particularly solid forms such as e.g.tablets or capsules are preferred. The content of the pharmaceuticallyactive compound(s) is advantageously in the range from 0.1 to 90 wt.-%,for example from 1 to 70 wt.-% of the composition as a whole.

Suitable tablets may be obtained, for example, by mixing one or morecompounds according to formula I with known excipients, for exampleinert diluents, carriers, disintegrants, adjuvants, surfactants, bindersand/or lubricants. The tablets may also consist of several layers. Theparticular excipients, carriers and/or diluents that are suitable forthe desired preparations will be familiar to the skilled man on thebasis of his specialist knowledge. The preferred ones are those that aresuitable for the particular formulation and method of administrationthat are desired. The preparations or formulations according to theinvention may be prepared using methods known per se that are familiarto the skilled man, such as for example by mixing or combining at leastone compound of formula I according to the invention, or apharmaceutically acceptable salt of such a compound, and one or moreexcipients, carriers and/or diluents.

Combination Therapy

The compounds of the invention may further be combined with one or more,preferably one additional therapeutic agent. According to one embodimentthe additional therapeutic agent is selected from the group oftherapeutic agents useful in the treatment of diseases or conditionsdescribed hereinbefore, in particular associated with metabolic diseasesor conditions such as for example diabetes mellitus, obesity, diabeticcomplications, hypertension, hyperlipidemia. Additional therapeuticagents which are suitable for such combinations include in particularthose which for example potentiate the therapeutic effect of one or moreactive substances with respect to one of the indications mentionedand/or which allow the dosage of one or more active substances to bereduced.

Therefore a compound of the invention may be combined with one or moreadditional therapeutic agents selected from the group consisting ofantidiabetic agents, agents for the treatment of overweight and/orobesity and agents for the treatment of high blood pressure, heartfailure and/or atherosclerosis.

Antidiabetic agents are for example metformin, sulphonylureas,nateglinide, repaglinide, thiazolidinediones, PPAR-(alpha, gamma oralpha/gamma) agonists or modulators, alpha-glucosidase inhibitors, DPPIVinhibitors, SGLT2-inhibitors, insulin and insulin analogues, GLP-1 andGLP-1 analogues or amylin and amylin analogues, cycloset, 11β-HSDinhibitors. Other suitable combination partners are inhibitors ofprotein tyrosinephosphatase 1, substances that affect deregulatedglucose production in the liver, such as e.g. inhibitors ofglucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogenphosphorylase, glucagon receptor antagonists and inhibitors ofphosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvatedehydrokinase, alpha2-antagonists, CCR-2 antagonists or glucokinaseactivators. One or more lipid lowering agents are also suitable ascombination partners, such as for example HMG-CoA-reductase inhibitors,fibrates, nicotinic acid and the derivatives thereof, PPAR-(alpha, gammaor alpha/gamma) agonists or modulators, PPAR-delta agonists, ACATinhibitors or cholesterol absorption inhibitors such as, bileacid-binding substances such as, inhibitors of ileac bile acidtransport, MTP inhibitors, or HDL-raising compounds such as CETPinhibitors or ABC1 regulators.

Therapeutic agents for the treatment of overweight and/or obesity arefor example antagonists of the cannabinoid1 receptor, MCH-1 receptorantagonists, MC4 receptor agonists, NPYS or NPY2 antagonists,β3-agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor.

Therapeutic agents for the treatment of high blood pressure, chronicheart failure and/or atherosclerosis are for example A-II antagonists orACE inhibitors, ECE inhibitors, diuretics, β-blockers, Ca-antagonists,centrally acting antihypertensives, antagonists of thealpha-2-adrenergic receptor, inhibitors of neutral endopeptidase,thrombocyte aggregation inhibitors and others or combinations thereofare suitable. Angiotensin II receptor antagonists are preferably usedfor the treatment or prevention of high blood pressure and complicationsof diabetes, often combined with a diuretic such as hydrochlorothiazide.

The dosage for the combination partners mentioned above is usually ⅕ ofthe lowest dose normally recommended up to 1/1 of the normallyrecommended dose.

Preferably, compounds of the present invention and/or pharmaceuticalcompositions comprising a compound of the present invention optionallyin combination with one or more additional therapeutic agents areadministered in conjunction with exercise and/or a diet.

Therefore, in another aspect, this invention relates to the use of acompound according to the invention in combination with one or moreadditional therapeutic agents described hereinbefore and hereinafter forthe treatment of diseases or conditions which may be affected or whichare mediated by the activation of the G-protein-coupled receptor GPR40,in particular diseases or conditions as described hereinbefore andhereinafter.

In yet another aspect the present invention relates a method fortreating a disease or condition mediated by the activation of theG-protein-coupled receptor GPR40 in a patient that includes the step ofadministering to the patient, preferably a human, in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention in combination with a therapeutically effective amountof one or more additional therapeutic agents described in hereinbeforeand hereinafter,

The use of the compound according to the invention in combination withthe additional therapeutic agent may take place simultaneously or atstaggered times.

The compound according to the invention and the one or more additionaltherapeutic agents may both be present together in one formulation, forexample a tablet or capsule, or separately in two identical or differentformulations, for example as a so-called kit-of-parts.

Consequently, in another aspect, this invention relates to apharmaceutical composition which comprises a compound according to theinvention and one or more additional therapeutic agents describedhereinbefore and hereinafter, optionally together with one or more inertcarriers and/or diluents.

Other features and advantages of the present invention will becomeapparent from the following more detailed Examples which illustrate, byway of example, the principles of the invention.

EXAMPLES

The terms “ambient temperature” and “room temperature” are usedinterchangeably and designate a temperature of about 20° C.

As a rule, ¹H-NMR and/or mass spectra have been obtained for thecompounds prepared.

Intermediates and Examples reported in the following bearing a basic oracidic group may be obtained as a corresponding salt or neutral compounddepending on the purification method and conditions employed. Salts canbe transformed into their neutral counterparts by standard proceduresknown to the one skilled in the art.

Analytical HPLC parameters employed for characterization of products(TFA denotes trifluoroacetic acid):

Method: 1 Device: Agilent 1200 with DA- and MS-Detector Column: SunfireC18, 3 × 30 mm, 2.5 μm Column Waters Supplier: Gradient % SolventSolvent [H₂O, % Solvent Flow Temperature Time [min] 0.1% TFA][Acetonitrile] [ml/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60

Intermediate 1 trans-2-(5-Bromo-pyridin-2-yl)-cyclopropanecarboxylicacid ethyl ester

Step 1: 5-Bromo-2-vinyl-pyridine

Na₂CO₃ solution (2 mol/L in water, 8.8 mL) is added to a flask chargedwith a stir bar, 5-bromo-2-iodo-pyridine (2.00 g), potassiumvinyltrifluoroborate (0.94 g), tetrahydro-furan (6 mL), and toluene (2mL) at room temperature. The mixture is purged with Ar for 5 min priorto the addition of1,1′-bis(diphenylphosphino)ferrocene-dichloro-palladium(II) (0.49 g).The mixture is stirred at 100° C. overnight. After cooling to roomtemperature, aqueous NH₄Cl solution is added, and the resulting mixtureis extracted with ethyl acetate. The combined extract is dried (MgSO₄)and concentrated. The residue is chromatographed on silica gel(cyclohexane/ethyl acetate 4:1→7:3) to give the title compound. Massspectrum (ESI⁺): m/z=184/186 (Br) [M+H]⁺.

Step 2: trans-2-(5-Bromo-pyridin-2-yl)-cyclopropanecarboxylic acid ethylester

5,10,15,20-Tetraphenyl-21H,23H-porphine cobalt(II) (28 mg),1-methylimidazole (0.52 g), and ethyl diazoacetate (13% indichloromethane; 2.0 mL) are added to a flask charged with a stir bar,5-bromo-2-vinyl-pyridine (0.39 g), and toluene (3.3 mL) at roomtemperature. The mixture is stirred at room temperature for 5 min andthen at 80° C. for 90 min. After cooling to room temperature, themixture is concentrated, and the residue is chromatographed on silicagel (cyclohexane/ethyl acetate 6:1→3:2) to give the racemic transconfigured title compound. Mass spectrum (ESI⁺): m/z=270/272 (Br)[M+H]⁺.

Intermediate 2 (1S,2S)-2-(5-Bromo-pyridin-2-yl)-cyclopropanecarboxylicacid ethyl ester

Step 1: 1-(5-Bromo-pyridin-2-yl)-2-chloro-ethanone

^(i)PrMgCl*LiCl (Turbo Grignard, 1.3 mol/L in tetrahydrofuran, 25.6 mL)is added dropwise to a flask charged with a stir bar,2-iodo-5-bromo-pyridine (9.00 g), and tetrahydrofuran (180 mL) andchilled to −30° C. The mixture is stirred in the cooling bath for 1 h.2-Chloro-N-methoxy-N-methylacetamide (4.58 g) dissolved intetrahydro-furan (20 mL) is added dropwise over 5 min. The mixture isstirred for 30 min and then quenched by the addition of aqueous 1 M HClsolution. The mixture is concentrated, and the aqueous residue isextracted with ethyl acetate. The combined extract is dried (MgSO₄) andconcentrated. The residue is chromatographed on silica gel(cyclohexane/ethyl acetate 20:1→1:1) to give the title compound. Massspectrum (ESI⁺): m/z=234/236/238 (Br+Cl) [M+H]⁺.

Step 2: (R)-1-(5-Bromo-pyridin-2-yl)-2-chloro-ethanol

Formic acid (3.9 mL) is added to a flask charged with a stir bar andtriethylamine (14.3 mL) and chilled in an ice bath. The mixture isstirred for 10 min and then added dropwise over 5 min to a flask chargedwith 1-(5-bromo-pyridin-2-yl)-2-chloro-ethanone (4.80 g),(1S,2S)—Cp*RhCl(TsNCHPhCHPhNH₂) (0.13 g; prepared from(1S,2S)-(+)-N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine andpentamethyl-cyclopentadienyl-rhodium chloride dimer as described in,e.g., Organometallics 2009, 28, 1435-1446 or Chem. Commun. 2015, 52,362-365; alternatively, the catalyst is prepared in situ by combiningthe two components in the reaction flask), and ethyl acetate (150 ml) at−45° C. The mixture is stirred at −30° C. for 90 min. Aqueous NaHCO₃solution is added, and the resulting mixture is stirred at roomtemperature. The mixture is extracted with ethyl acetate, and thecombined extract is dried (MgSO₄) and concentrated. The residue ischromatographed on silica gel (cyclohexane/ethyl acetate 50:1→6:1) togive the title compound with an enantiomeric excess (ee) of 75 to 95%.Mass spectrum (ESI⁺): m/z=236/238/240 (Br+Cl) [M+H]⁺.

Step 3: (R)-5-Bromo-2-oxiranyl-pyridine

Aqueous NaOH solution (4 mol/L, 25 mL) is added to a flask charged witha stir bar, (R)-1-(5-bromo-pyridin-2-yl)-2-chloro-ethanol (3.0 g), andtetrahydrofuran (100 mL) at room temperature. The mixture is stirredovernight prior to the addition of brine. The organic phase isseparated, and the aqueous phase is extracted twice withtetrahydrofuran. The combined organic phase is dried (MgSO₄) andconcentrated to give the crude title compound that is used as is in thefollowing step. Mass spectrum (ESI⁺): m/z=200/202 (Br) [M+H]⁺.

Step 4: (1S,2S)-2-(5-Bromo-pyridin-2-yl)-cyclopropanecarboxylic acidethyl ester

A solution of sodium tert-butoxide (7.9 g) in tetrahydrofuran (80 mL) isadded dropwise over 30 min to a flask charged with a stir bar,triethylphosphonoacetate (16.3 mL), and toluene (80 mL) at roomtemperature. The mixture is stirred for 30 min and then added dropwiseover 4 h to a solution of (R)-5-bromo-2-oxiranyl-pyridine (5.5 g) intoluene (350 mL) at 90° C. The mixture is stirred for 1 h and thencooled to room temperature. The mixture is washed with aqueous 1 M H₃PO₄solution and brine and dried (MgSO₄). The mixture is concentrated, andthe residue is chromatographed on silica gel (petrol ether/ethylacetate) to give the title compound. Mass spectrum (ESI⁺): m/z=270/272(Br) [M+H]⁺.

Intermediate 3 (1S,2S)-2-(5-Bromo-pyridin-2-yl)-cyclopropanecarboxylicacid

Aqueous 4 M NaOH solution (7.3 mL) is added to a flask charged with astir bar, (1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acidethyl ester (4.89 g), and tetrahydrofuran (30 mL) at room temperature.The mixture is stirred at 60° C. for 4 h. After cooling to roomtemperature, water is added and most of the tetrahydrofuran isevaporated. Aqueous 4 M HCl solution is added dropwise to adjust the pHvalue to ca. 4. The mixture is stirred overnight. The precipitate isseparated by filtration, washed with water, and dried in a desiccator togive the title compound.

The enantiomeric purities (ee) of batches of Intermediate 3, obtainedfrom Intermediate 2 and hydrolyzed as described above, are commonlybetween 75% and 95%.

The enantiomeric purity of batches of Intermediate 3 may be increasedto >95% ee by employing the following procedure:

(S)-1-Phenylethylamine (1.85 mL) is added to a solution of(1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid (3.51 g) inisopropanol (55 mL) at 80° C. The solution is stirred for 15 min andthen left standing without stirring at room temperature overnight. Theprecipitate is separated by filtration, washed with isopropanol, anddried at 40° C. to give the (S)-1-phenylethylammonium(1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylate (if thediasteromeric purity (de) of the ammonium salt is not sufficient theprecipitate is again recrystallized from isopropanol).

The carboxylate (2.79 g) is suspended in ethyl acetate (50 mL), andaqueous 4 M HCl solution (7.7 mL) is added. The mixture is stirred untilall solid is dissolved. The organic phase is separated and washed with 4M HCl solution, water, and brine. The organic phase is dried (MgSO₄) andconcentrated to give a batch of(1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid. Theaqueous phase is freeze-dried and then chromatographed on silica gel(MPLC, dichloromethane/methanol) to give another batch of(1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid.

Intermediate 4(R)-4-[2,6-Dimethyl-4-(2-methyl-2H-tetrazol-5-yl)-phenyl]-indan-1-ylamine

Step 1: (S)-4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-ol

Potassium acetate (2.0 g) is added to a flask charged with a stir bar,(S)-4-bromo-indan-1-ol (2.5 g; for preparation see WO2013/144098),bis(pinacolato)diboron (3.3 g), and 1,4-dioxane (50 mL) at roomtemperature. The mixture is purged with Ar for 5 min prior to theaddition of 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II)(0.4 g). The mixture is stirred at 100° C. overnight. After cooling toroom temperature, the mixture is diluted with ethyl acetate and washedwith aqueous NH₄Cl solution and brine and dried (MgSO₄). The solvent isevaporated, and the residue is chromatographed on silica gel (petrolether/ethyl acetate) to give the title compound. Mass spectrum (ESI⁺):m/z=243 [M−OH]⁺.

Step 2:(S)-4-[2,6-Dimethyl-4-(2-methyl-2H-tetrazol-5-yl)-phenyl]-indan-1-ol

Dicyclohexyl-(2′,6′-dimethoxy-biphenyl-2-yl)-phosphane (SPhos, 30 mg)and K₃PO₄ (2 M in water, 0.8 mL) are added to a flask charged with astir bar,(S)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-ol (0.10g), 5-(4-bromo-3,5-dimethyl-phenyl)-2-methyl-2H-tetrazole (0.12 g; forpreparation see WO2013/144097), and toluene (2 mL) at room temperature.The mixture is purged with Ar for 5 min prior to the addition ofpalladium(II) acetate (8 mg). The mixture is stirred at 100° C. for 1 h.After cooling to room temperature, the mixture is diluted with diethylether and washed with aqueous NH₄Cl solution and dried (MgSO₄). Thesolvent is evaporated, and the residue is chromatographed on silica gel(petrol ether/ethyl acetate) to give the title compound. Mass spectrum(ESI⁺): m/z=321 [M+H]⁺.

Step 3:2-{(R)-4-[2,6-Dimethyl-4-(2-methyl-2H-tetrazol-5-yl)-phenyl]-indan-1-yl}-isoindole-1,3-dione

Di-tert-butyl-azodicarboxylate (0.70 g) is added to a flask charged witha stir bar,(S)-4-[2,6-dimethyl-4-(2-methyl-2H-tetrazol-5-yl)-phenyl]-indan-1-ol(0.72 g), phthalimide (0.37 g), tri-n-butyl-phosphine (0.67 g), andtetrahydrofuran (10 mL) chilled in an ice bath. The ice bath is removed,and the mixture is stirred at room temperature overnight. The mixture isdiluted with ethyl acetate and washed with aqueous NaHCO₃ solution anddried (MgSO₄). The solvent is evaporated, and the residue ischromatographed on silica gel (petrol ether/ethyl acetate) to give thetitle compound. Mass spectrum (ESI⁺): m/z=450 [M+H]⁺.

Step 4:(R)-4-[2,6-Dimethyl-4-(2-methyl-2H-tetrazol-5-yl)-phenyl]-indan-1-ylamine

Hydrazine hydrate (0.83 g) is added to a flask charged with a stir bar,2-{(R)-4-[2,6-dimethyl-4-(2-methyl-2H-tetrazol-5-yl)-phenyl]-indan-1-yl}-isoindole-1,3-dione(0.81 g), and methanol (5 mL) at room temperature. The mixture isstirred at room temperature overnight. The mixture is diluted with ethylacetate and filtered. The solvent is evaporated, and the residue ispurified by HPLC on reversed phase (acetonitrile, water, ammonia) togive the title compound. Mass spectrum (ESI⁺): m/z=303 [M−NH₂]⁺.

Intermediate 54-[4-((R)-1-Amino-indan-4-yl)-3,5-dimethyl-phenoxy]-2-methyl-butan-2-ol

Step 1:(S)-4-[4-(3-Hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenyl]-indan-1-ol

The title compound is prepared from (S)-4-bromo-indan-1-ol (forpreparation see WO2013/144098) and4-(3-hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenylboronic acid (forpreparation see WO2015/44073) following a procedure analogous to thatdescribed in Step 2 of Intermediate 4. Mass spectrum (ESI⁺): m/z=323[M−NH₂]⁺.

Step 2:2-{(R)-4-[4-(3-Hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenyl]-indan-1-yl}-isoindole-1,3-dione

The title compound is prepared from(S)-4-[4-(3-hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenyl]-indan-1-ol andphthalimide following a procedure analogous to that described in Step 3of Intermediate 4. Mass spectrum (ESI⁺): m/z=452 [M−NH₂]⁺.

Step 3:4-[4-((R)-1-Amino-indan-4-yl)-3,5-dimethyl-phenoxy]-2-methyl-butan-2-ol

The title compound is prepared from2-{(R)-4-[4-(3-hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenyl]-indan-1-yl}-isoindole-1,3-dionefollowing a procedure analogous to that described in Step 4 ofIntermediate 4. Mass spectrum (ESI⁺): m/z=323 [M−NH₂]⁺.

Intermediate 6(R)-4-[2,6-Dimethyl-4-(2-methyl-2H-tetrazol-5-yl)-phenyl]-7-fluoro-indan-1-ylamine

Step 1:(S)-4-[2,6-Dimethyl-4-(2-methyl-2H-tetrazol-5-yl)-phenyl]-7-fluoro-indan-1-ol

The title compound is prepared from(S)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-7-fluoro-indan-1-ol(is obtained from (S)-4-bromo-7-fluoro-indan-1-ol employing theprocedure described in Step 1 of Intermediate 4) and5-(4-bromo-3,5-dimethyl-phenyl)-2-methyl-2H-tetrazole following aprocedure analogous to that described in Step 2 of Intermediate 4. Massspectrum (ESI⁺): m/z=339 [M+H]⁺.

Step 2:5-[4-((R)-1-Azido-7-fluoro-indan-4-yl)-3,5-dimethyl-phenyl]-2-methyl-2H-tetrazole

Diphenylphosphoryl azide (2.3 mL) is added over a period of 2 h to aflask charged with a stir bar,(S)-4-[2,6-dimethyl-4-(2-methyl-2H-tetrazol-5-yl)-phenyl]-7-fluoro-indan-1-ol(3.45 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (2.35 mL), and toluene (75mL) chilled in an ice bath. The cooling bath is removed, and the mixtureis stirred at room temperature overnight. The mixture is diluted withethyl acetate and washed with water and brine and dried (Na₂SO₄). Thesolvent is evaporated, and the residue is chromatographed on silica gel(cyclohexane/ethyl acetate 9:1→3:2) to give the title compound. Massspectrum (ESI⁺): m/z=364 [M+H]⁺.

Step 3:(R)-4-[2,6-Dimethyl-4-(2-methyl-2H-tetrazol-5-yl)-phenyl]-7-fluoro-indan-1-ylamine

A flask charged with5-[4-((R)-1-azido-7-fluoro-indan-4-yl)-3,5-dimethyl-phenyl]-2-methyl-2H-tetrazole(2.33 g), 10% palladium on carbon (0.4 g), and ethanol (75 mL) is shakenunder hydrogen atmosphere (3 bar) at room temperature for 7 h. Themixture is filtered, and the filtrate is concentrated to give the titlecompound. Mass spectrum (ESI⁺): m/z=338 [M+H]⁺.

Intermediate 74-[4-((R)-1-Amino-7-fluoro-indan-4-yl)-3,5-dimethyl-phenoxy]-2-methyl-butan-2-ol

Step 1:(S)-7-Fluoro-4-[4-(3-hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenyl]-indan-1-ol

The title compound is prepared from (S)-4-bromo-7-fluoro-indan-1-ol (forpreparation see WO2013/144097) and4-(3-hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenylboronic acid (forpreparation see WO2015/44073) following a procedure analogous to thatdescribed in Step 2 of Intermediate 4. Mass spectrum (ESI⁺): m/z=341[M−OH]⁺.

Step 2:4-[4-((R)-1-Azido-7-fluoro-indan-4-yl)-3,5-dimethyl-phenoxy]-2-methyl-butan-2-ol

The title compound is prepared from(S)-7-fluoro-4-[4-(3-hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenyl]-indan-1-olfollowing a procedure analogous to that described in Step 2 ofIntermediate 6. Mass spectrum (ESI⁺): m/z=406 [M+Na]⁺.

Step 3:4-[4-((R)-1-Amino-7-fluoro-indan-4-yl)-3,5-dimethyl-phenoxy]-2-methyl-butan-2-ol

The title compound is prepared from4-[4-((R)-1-azido-7-fluoro-indan-4-yl)-3,5-dimethyl-phenoxy]-2-methyl-butan-2-olfollowing a procedure analogous to that described in Step 3 ofIntermediate 6. Mass spectrum (ESI⁺): m/z=341 [M−NH₂]⁺.

Intermediate 8 (R)-7-Fluoro-4-trimethylsilanyl-indan-1-ylamine

Step 1: (S)-7-Fluoro-4-trimethylsilyl-indan-1-ol

n-Butyl lithium (1.6 mol/L in hexanes; 60 mL) is added dropwise to aflask charged with a stir bar, (S)-4-bromo-7-fluoro-indan-1-ol (10.0 g),and tetrahydrofuran (80 mL) cooled to −75° C. The mixture is stirredbelow −70° C. for 45 min prior to the addition of chlorotrimethylsilane(12 mL). The mixture is warmed to room temperature overnight. Themixture is cooled to −50° C., treated with 4 M aqueous HCl solution (25mL), and warmed to room temperature. The mixture is concentrated, andthe residue is chromatographed on silica gel (cyclohexane/ethyl acetate3:1→2:3) to give the title compound. Mass spectrum (ESI⁺): m/z=207[M−OH]⁺.

Step 2: ((R)-1-Azido-7-fluoro-indan-4-yl)-trimethyl-silane

The title compound is prepared from(S)-7-fluoro-4-trimethylsilanyl-indan-1-ol following a procedureanalogous to that described in Step 2 of Intermediate 6. Mass spectrum(ESI⁺): m/z=207 [M−N₃]⁺.

Step 3: (R)-7-Fluoro-4-trimethylsilyl-indan-1-ylamine

The title compound is prepared from((R)-1-azido-7-fluoro-indan-4-yl)-trimethyl-silane following a procedureanalogous to that described in Step 3 of Intermediate 6. Mass spectrum(ESI⁺): m/z=224 [M+H]⁺.

Intermediate 9(1S,2S)-2-{5-[(R)-7-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-ylamino]-pyridin-2-yl}-cyclopropanecarboxylicacid methyl ester

Step 1:(1S,2S)-2-[5-((R)-7-Fluoro-4-trimethylsilanyl-indan-1-ylamino)-pyridin-2-yl]-cyclopropanecarboxylicacid

The title compound is prepared from(1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid ethyl esterand (R)-7-fluoro-4-trimethylsilyl-indan-1-ylamine following a procedureanalogous to that described for Example 4; the reaction is conducted at100° C. instead of 85° C., and the ester group is hydrolyzed under theconditions. Mass spectrum (ESI⁺): m/z=385 [M+H]⁺.

Step 2:(1S,2S)-2-[5-((R)-7-Fluoro-4-trimethylsilanyl-indan-1-ylamino)-pyridin-2-yl]-cyclopropanecarboxylicacid methyl ester

(Trimethylsilyl)diazomethane (2 mol/L in hexane; 2.3 mL) is added to amixture of(1S,2S)-2-[5-((R)-7-fluoro-4-trimethylsilanyl-indan-1-ylamino)-pyridin-2-yl]-cycloropanecarboxylicacid (0.90 g), methanol (10 mL), and dichloromethane (30 mL) chilled inan ice bath. The mixture is stirred for 15 min in the cooling bath andthen at ambient temperature for 30 min. The mixture is concentrated, andthe residue is chromatographed on silica gel (cyclohexane/ethyl acetate50:1→3:1) to give the title compound. Mass spectrum (ESI⁺): m/z=399[M+H]⁺.

Alternatively, the title compound is obtained from(R)-7-fluoro-4-trimethylsilyl-indan-1-ylamine and(1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid methylester employing CuI, 2-(2,6-dimethylphenylamino)-2-oxoacetic acid,K₃PO₄, and dimethylsulfoxide at 100° C. as described in Org. Lett. 2012,14, 3056-9.

Step 3:(1S,2S)-2-[5-((R)-7-Fluoro-4-iodo-indan-1-ylamino)-pyridin-2-yl]-cyclopropanecarboxylicacid methyl ester

Iodine monochloride (1 mol/L in dichloromethane; 8 mL) is added to(1S,2S)-2-[5-((R)-7-fluoro-4-trimethylsilanyl-indan-1-ylamino)-pyridin-2-yl]-cyclopropanecarboxylicacid methyl ester (1.60 g) in dichloromethane (10 mL) chilled in an icebath. The solution is stirred in the cooling bath for 30 min. Aqueous 1M NaHCO₃ solution is added, and the resulting mixture is extracted withethyl acetate. The combined extract is washed with water, saturatedaqueous Na₂S₂O₃ solution, and brine and dried (Na₂SO₄). The solvent isevaporated, and the residue is chromatographed on silica gel(cyclohexane/ethyl acetate 50:1→5:1) to give the title compound. Massspectrum (ESI⁺): m/z=453 [M+H]⁺.

Step 4:(1S,2S)-2-{5-[(R)-7-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-ylamino]-pyridin-2-yl}-cyclopropanecarboxylicacid methyl ester

The title compound is prepared from(1S,2S)-2-[5-((R)-7-fluoro-4-iodo-indan-1-ylamino)-pyridin-2-yl]-cyclopropanecarboxylicacid methyl ester following a procedure analogous to that described inStep 1 of Intermediate 4. Mass spectrum (ESI⁺): m/z=453 [M+H]⁺.

Intermediate 10 ((R)-4-Bromo-7-fluoro-indan-1-yl)-carbamic acidtert-butyl ester

Step 1: 2-((R)-4-Bromo-7-fluoro-indan-1-yl)-isoindole-1,3-dione

The title compound is prepared from (S)-4-bromo-7-fluoro-indan-1-ol andphthalimide following a procedure analogous to that described in Step 3of Intermediate 4. Mass spectrum (ESI⁺): m/z=360/362 (Br) [M+H]⁺.

Step 2: (R)-4-Bromo-7-fluoro-indan-1-ylamine

The title compound is prepared from2-((R)-4-bromo-7-fluoro-indan-1-yl)-isoindole-1,3-dione following aprocedure analogous to that described in Step 4 of Intermediate 4; thecompound may be converted into the hydrogen chloride salt by treatmentwith HCl (5 mol/L in isopropanol) in ethyl acetate. Mass spectrum(ESI⁺): m/z=230/232 (Br) [M+H]⁺.

Step 3: ((R)-4-Bromo-7-fluoro-indan-1-yl)-carbamic acid tert-butyl ester

Triethylamine (9.3 mL) and di-tert-butyl dicarbonate (7.12 g) are addedto a solution of the hydrogen chloride salt of(R)-4-bromo-7-fluoro-indan-1-ylamine (8.70 g) in tetrahydrofuran (100mL) at room temperature. The solution is stirred at room temperatureovernight. Water is added, and the resulting mixture is extracted withethyl acetate. The combined extract is dried (MgSO₄) and concentrated togive the title compound. Mass spectrum (ESI⁺): m/z=273/275 (Br)[M-tert-butyl]⁺.

Step 4:[(R)-7-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yl]-carbamicacid tert-butyl ester

The title compound is prepared from((R)-4-bromo-7-fluoro-indan-1-yl)-carbamic acid tert-butyl esterfollowing a procedure analogous to that described in Step 1 ofIntermediate 4. Mass spectrum (ESI⁺): m/z=322 [M-tert-butyl]⁺.

Intermediate 11(3R,4R)-4-[4-((R)-1-Amino-7-fluoro-indan-4-yl)-3,5-dimethyl-phenoxy]-tetrahydro-furan-3-ol

Step 1:[(3R,4R)-4-(4-Bromo-3,5-dimethyl-phenoxy)-tetrahydro-furan-3-yloxy]-tert-butyl-dimethyl-silane

CuI (0.12 g) and 1,10-phenanthroline (0.23 g) are added to a flaskcharged with a stir bar, 2-bromo-5-iodo-m-xylene (2.00 g),(3R,4R)-4-(tert-butyl-dimethyl-silanyloxy)-tetrahydrofuran-3-ol (1.72g), Cs₂CO₃ (4.11 g), and toluene (10 mL) at room temperature. Themixture is stirred at 115° C. overnight. After cooling to roomtemperature, water is added, and the resulting mixture is extracted withethyl acetate. The combined extract is washed with aqueous 1 M HClsolution and dried (MgSO₄). The solvent is evaporated, and the residueis chromatographed on silica gel (cyclohexane/ethyl acetate 49:1) togive the title compound. Mass spectrum (ESI⁺): m/z=401/403 (Br) [M+H]⁺.

Step 2:((R)-4-{4-[(3R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-tetrahydro-furan-3-yloxy]-2,6-dimethyl-phenyl}-7-fluoro-indan-1-yl)-carbamicacid tert-butyl ester

A vial charged with a stir bar,[(3R,4R)-4-(4-bromo-3,5-dimethyl-phenoxy)-tetrahydro-furan-3-yloxy]-tert-butyl-dimethyl-silane(0.80 g),[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yl]carbamicacid tert-butyl ester (0.64 g), K₃PO₄ (0.96 g), water (4.3 mL), and1,4-dioxane (13 mL) is purged with Ar for 10 min.Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(PdCl₂(Amphos)₂; 0.10 g) is added, and the mixture is stirred at 80° C.for 1 h. After cooling to room temperature, water is added, and themixture is extracted with ethyl acetate. The combined extract is dried(MgSO₄) and concentrated to give the crude product that is used as is inthe next step. Mass spectrum (ESI⁺): m/z=516 [M+H]⁺.

Step 3:(3R,4R)-4-[4-((R)-1-Amino-7-fluoro-indan-4-yl)-3,5-dimethyl-phenoxy]-tetrahydro-furan-3-ol

HCl solution (4 mol/L in 1,4-dioxane, 10 mL) is added to a solution of((R)-4-{4-[(3R,4R)-4-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-3-yloxy]-2,6-dimethyl-phenyl}-7-fluoro-indan-1-yl)-carbamicacid tert-butyl ester (1.56 g) in 1,4-dioxane (5 mL) at roomtemperature. The solution is stirred at room temperature for 1 h andthen concentrated. The residue is purified by HPLC(acetonitrile/water/trifluoroacetic acid) to give the title compound.Mass spectrum (ESI⁺): m/z=341 [M−NH₂]⁺.

Intermediate 12(R)-7-Fluoro-4-[4-(3-methanesulfonyl-propoxy)-2,6-dimethyl-phenyl]-indan-1-ylamine

Step 1:{(R)-7-Fluoro-4-[4-(3-methanesulfonyl-propoxy)-2,6-dimethyl-phenyl]-indan-1-yl}-carbamicacid tert-butyl ester

The title compound is prepared from2-bromo-5-(3-methanesulfonyl-propoxy)-1,3-dimethyl-benzene (forpreparation see WO2013/178575) and[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yl]-carbamicacid tert-butyl ester following a procedure analogous to that describedin Step 2 of Intermediate 11. Mass spectrum (ESI⁺): m/z=436[M-tert-butyl]⁺.

Step 2:(R)-7-Fluoro-4-[4-(3-methanesulfonyl-propoxy)-2,6-dimethyl-phenyl]-indan-1-ylamine

The title compound is prepared from{(R)-7-fluoro-4-[4-(3-methanesulfonyl-propoxy)-2,6-dimethyl-phenyl]-indan-1-yl}-carbamicacid tert-butyl ester following a procedure analogous to that describedin Step 3 of Intermediate 11. Mass spectrum (ESI⁺): m/z=375 [M−NH₂]⁺.

Intermediate 13 2-((R)-4-Bromo-indan-1-yl)-isoindole-1,3-dione

The title compound is prepared from (S)-4-bromo-indan-1-ol following aprocedure analogous to that described in Step 3 of Intermediate 4. Massspectrum (ESI⁺): m/z=342/344 (Br) [M+H]⁺.

Intermediate 14 (R)-4-(3-Fluoro-4-methoxy-phenyl)-indan-1-ylamine

Step 1:2-[(R)-4-(3-Fluoro-4-methoxy-phenyl)-indan-1-yl]-isoindole-1,3-dione

A vial charged with a stir bar,2-((R)-4-bromo-indan-1-yl)-isoindole-1,3-dione (0.50 g),3-fluoro-4-methoxy-phenylboronic acid (0.28 g),dicyclohexyl-(2′,6′-dimethoxy-biphenyl-2-yl)-phosphane (30 mg), K₃PO₄ (2mol/L in water, 4.5 mL), and toluene (10 mL) is purged with Ar for 10min. Pd(OAc)₂ (8 mg) is added, and the mixture is stirred at 110° C. for30 min. After cooling to room temperature, the mixture is filtered overCelite, and the filtrate is extracted with ethyl acetate. The combinedextract is washed with aqueous 1 M H₃PO₄ solution and brine, dried(MgSO₄), and concentrated to give the crude product that is used as isin the next step. Mass spectrum (ESI⁺): m/z=388 [M+H]⁺.

Step 2: (R)-4-(3-Fluoro-4-methoxy-phenyl)-indan-1-ylamine

The title compound is prepared from2-[(R)-4-(3-fluoro-4-methoxy-phenyl)-indan-1-yl]-isoindole-1,3-dionefollowing a procedure analogous to that described in Step 4 ofIntermediate 4. Mass spectrum (ESI⁺): m/z=241 [M−NH₂]⁺.

Intermediate 15(R)-4-[4-(5-Methoxy-pyrazin-2-yl)-phenyl]-indan-1-ylamine

Step 1:2-{(R)-4-[4-(5-Methoxy-pyrazin-2-yl)-phenyl]-indan-1-yl}-isoindole-1,3-dione

The title compound is prepared from2-((R)-4-bromo-indan-1-yl)-isoindole-1,3-dione and4-(5-methoxy-pyrazin-2-yl)-phenylboronic acid following a procedureanalogous to that described in Step 1 of Intermediate 14. Mass spectrum(ESI⁺): m/z=448 [M+H]⁺.

Step 2: (R)-4-[4-(5-Methoxy-pyrazin-2-yl)-phenyl]-indan-1-ylamine

The title compound is prepared from2-{(R)-4-[4-(5-methoxy-pyrazin-2-yl)-phenyl]-indan-1-yl}-isoindole-1,3-dionefollowing a procedure analogous to that described in Step 4 ofIntermediate 4. Mass spectrum (ESI⁺): m/z=301 [M−NH₂]⁺.

Intermediate 16(R)-4-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-indan-1-ylamine

Step 1:2-{(R)-4-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-indan-1-yl}-isoindole-1,3-dione

The title compound is prepared from2-((R)-4-bromo-indan-1-yl)-isoindole-1,3-dione and4-(5-methyl-1,3,4-oxadiazol-2-yl)-phenylboronic acid following aprocedure analogous to that described in Step 1 of Intermediate 14. Massspectrum (ESI⁺): m/z=422 [M+H]⁺.

Step 2:(R)-4-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-indan-1-ylamine

The title compound is prepared from2-{(R)-4-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]indan-1-yl}-isoindole-1,3-dionefollowing a procedure analogous to that described in Step 4 ofIntermediate 4. Mass spectrum (ESI⁺): m/z=275 [M−NH₂]⁺.

Example 1trans-2-(5-{(R)-7-Fluoro-4-[4-(3-hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenyl]-indan-1-ylamino}-pyridin-2-yl)-cyclopropanecarboxylicacid (ca. 1:1 mixture of trans-diastereomers with respect tocyclopropane)

A vial charged with a stir bar, sodium tert-butoxide (0.29 g),4-[4-((R)-1-amino-7-fluoro-indan-4-yl)-3,5-dimethyl-phenoxy]-2-methyl-butan-2-ol(0.43 g), trans-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acidethyl ester (0.32 g), and 1,4-dioxane (5 mL) is purged with Ar for 5min.Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II)(BRETTPHOS Pd G1 methyl-tert-butyl ether adduct; 48 mg) is added, andthe mixture is stirred at 100° C. for 2 h. After cooling to roomtemperature, aqueous KOH solution (4 mol/L, 0.4 mL) is added, and themixture is stirred at 50° C. overnight. The mixture is filtered, and thefiltrate is chromatographed (HPLC, acetonitrile, water andtrifluoroacetic acid as eluent) to give the title compound astrifluoroacetic acid salt that can be freed from trifluoroacetic acidemploying standard procedures. LC (method 1): t_(R)=0.92 min; Massspectrum (ESI⁻): m/z=517 [M−H]⁻.

Example 2(1S,2S)-2-(5-{(R)-7-Fluoro-4-[4-(3-hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenyl]-indan-1-ylamino}-pyridin-2-yl)-cyclopropanecarboxylicacid

A flask charged with a stir bar,4-[4-((R)-1-amino-7-fluoro-indan-4-yl)-3,5-dimethyl-phenoxy]-2-methyl-butan-2-ol(3.90 g), (1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid(2.74 g), and toluene (120 mL) is purged with Ar for 15 min.Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II)(BRETTPHOS Pd G1 methyl-tert-butyl ether adduct; 0.88 g),2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(0.58 g), and sodium tert-butoxide (5.48 g) are added, and the mixtureis stirred at 100° C. for 75 min. After cooling to room temperature,ethyl acetate, water, and acetic acid (3.1 mL) are added, and themixture is vigorously stirred for 10 min. The aqueous phase (pH valueca. 4) is separated and discarded, and water and aqueous 2 M NaHCO₃solution (16.5 mL) is added to the organic phase. After vigorousstirring for 10 min, the organic phase is separated and discarded, andthe aqueous phase (pH value ca. 10) is freed form residues of ethylacetate by evaporation. The aqueous phase is chilled in an ice bath, andacetic acid (3.1 mL) is added with stirring. The mixture is stirredovernight, and the precipitate is separated by filtration and washedwith water. The precipitate is taken up in ethyl acetate and dried(MgSO₄), and the solvent is evaporated to give the title compound. Incase the title compound is not sufficiently pure after this procedure,the product is additionally chromatographed on silica gel. LC (method1): t_(R)=0.92 min; Mass spectrum (ESI⁻): m/z=517 [M−H]⁻.

Alternatively, the title compound is obtained after chromatographicresolution of the diasteromeric mixture oftrans-2-(5-{(R)-7-fluoro-4-[4-(3-hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenyl]-indan-1-ylamino}-pyridin-2-yl)-cyclopropanecarboxylicacid (ca. 1:1 mixture of trans-diastereomers with respect tocyclopropane) employing supercritical fluid chromatography on chiralphase (column: Amylose SA (YMC), 5 μm, 250 mm×20 mm; eluent:scCO₂/isopropanol 75:25, 60 mL/min, 40° C., 150 bar):(1S,2S)-2-(5-{(R)-7-Fluoro-4-[4-(3-hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenyl]-indan-1-ylamino}-pyridin-2-yl)-cyclopropanecarboxylicacid: t_(R)=6.90 min(1R,2R)-2-(5-{(R)-7-Fluoro-4-[4-(3-hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenyl]-indan-1-ylamino}-pyridin-2-yl)-cyclopropanecarboxylicacid: t_(R)=7.89 min.

Example 3(1R,2R)-2-(5-{(R)-7-Fluoro-4-[4-(3-hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenyl]-indan-1-ylamino}-pyridin-2-yl)-cyclopropanecarboxylicacid

The title compound is obtained after chromatographic resolution of thediasteromeric mixture oftrans-2-(5-{(R)-7-fluoro-4-[4-(3-hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenyl]-indan-1-ylamino}-pyridin-2-yl)-cyclopropanecarboxylicacid (ca. 1:1 mixture of trans-diastereomers with respect tocyclopropane) employing supercritical fluid chromatography on chiralphase (column: Amylose SA (YMC), 5 μm, 250 mm×20 mm; eluent:scCO₂/isopropanol 75:25, 60 mL/min, 40° C., 150 bar):(1S,2S)-2-(5-{(R)-7-Fluoro-4-[4-(3-hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenyl]-indan-1-ylamino}-pyridin-2-yl)-cyclopropanecarboxylicacid: t_(R)=6.90 min(1R,2R)-2-(5-{(R)-7-Fluoro-4-[4-(3-hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenyl]-indan-1-ylamino}-pyridin-2-yl)-cyclopropanecarboxylicacid: t_(R)=7.89 min.

Mass spectrum (ESI⁻): m/z=517 [M−H]⁻.

Example 4(1S,2S)-2-(5-{(R)-7-Fluoro-4-[4-(3-methanesulfonyl-propoxy)-2,6-dimethyl-phenyl]-indan-1-ylamino}-pyridin-2-yl)-cyclopropanecarboxylicacid

A vial charged with a stir bar,(R)-7-fluoro-4-[4-(3-methanesulfonyl-propoxy)-2,6-dimethyl-phenyl]-indan-1-ylamine(125 mg), (1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid(77 mg), and 1,4-dioxane (3 mL) is purged with Ar for 10 min. Sodiumtert-butoxide (184 mg) andchloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II)(BRETTPHOS Pd G1 methyl-tert-butyl ether adduct; 13 mg) are added, andthe mixture is stirred at 85° C. for 30 min. After cooling to roomtemperature, the mixture is filtered, the filtrate is diluted with amixture of methanol, tetrahydrofuran, and triethylamine and submitted toHPLC (acetonitrile, water, and ammonia as eluent) to give the titlecompound. LC (method 1): t_(R)=0.88 min; Mass spectrum (ESI⁻): m/z=551[M−H]⁻.

Example 5(1S,2S)-2-(5-{(R)-7-Fluoro-4-[4-((3R,4R)-4-hydroxy-tetrahydro-furan-3-yloxy)-2,6-dimethyl-phenyl]-indan-1-ylamino}-pyridin-2-yl)-cyclopropanecarboxylicacid

The title compound is prepared from(1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid and(3R,4R)-4-[4-((R)-1-amino-7-fluoro-indan-4-yl)-3,5-dimethyl-phenoxy]-tetrahydro-furan-3-olfollowing a procedure analogous to that described for Example 4. LC(method 1): t_(R)=0.85 min; Mass spectrum (ESI⁺): m/z=519 [M+H]⁺.

Example 6(1S,2S)-2-(5-{(R)-4-[2,6-Dimethyl-4-(2-methyl-2H-tetrazol-5-yl)-phenyl]-indan-1-ylamino}-pyridin-2-yl)-cyclopropanecarboxylicacid

A vial charged with a stir bar,(R)-4-[2,6-dimethyl-4-(2-methyl-2H-tetrazol-5-yl)-phenyl]-indan-1-ylamine(75 mg), (1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid(60 mg), and 2-methylbutan-2-ol (2 mL) is purged with Ar for 10 min.Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II)(BRETTPHOS Pd G1 methyl-tert-butyl ether adduct; 9 mg) and sodiumtert-pentoxide (100 mg) are added, and the mixture is stirred at 85° C.for 90 min. After cooling to room temperature, the mixture is dilutedwith tetrahydrofuran and acetic acid (50 μL) and filtered. The filtrateis submitted to HPLC (acetonitrile, water, and trifluoroacetic acid aseluent) to give the title compound. LC (method 1): t_(R)=0.90 min; Massspectrum (ESI⁺): m/z=481 [M+H]⁺.

Example 7(1S,2S)-2-(5-{(R)-4-[4-(3-Hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenyl]-indan-1-ylamino}-pyridin-2-yl)-cyclopropanecarboxylicacid

The title compound is prepared from(1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid and4-[4-((R)-1-amino-indan-4-yl)-3,5-dimethyl-phenoxy]-2-methyl-butan-2-olfollowing a procedure analogous to that described for Example 6. LC(method 1): t_(R)=0.91 min; Mass spectrum (ESI⁺): m/z=501 [M+H]⁺.

Example 8(1S,2S)-2-{5-[(R)-4-(3-Fluoro-4-methoxy-phenyl)-indan-1-ylamino]-pyridin-2-yl}-cyclopropanecarboxylicacid

The title compound is prepared from(1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid and(R)-4-(3-fluoro-4-methoxy-phenyl)-indan-1-ylamine following a procedureanalogous to that described for Example 6. LC (method 1): t_(R)=0.88min; Mass spectrum (ESI⁺): m/z=419 [M+H]⁺.

Example 9(1S,2S)-2-(5-{(R)-4-[4-(5-Methoxy-pyrazin-2-yl)-phenyl]-indan-1-ylamino}-pyridin-2-yl)-cyclopropanecarboxylicacid

The title compound is prepared from(1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid and(R)-4-[4-(5-methoxy-pyrazin-2-yl)-phenyl]-indan-1-ylamine following aprocedure analogous to that described for Example 6. LC (method 1):t_(R)=0.93 min; Mass spectrum (ESI⁺): m/z=479 [M+H]⁺.

Example 10(1S,2S)-2-(5-{(R)-4-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-indan-1-ylamino}-pyridin-2-yl)-cyclopropanecarboxylicacid

The title compound is prepared from(1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid and(R)-4-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-indan-1-ylaminefollowing a procedure analogous to that described for Example 6. LC(method 1): t_(R)=0.84 min; Mass spectrum (ESI⁺): m/z=453 [M+H]⁺.

The following compounds compiled in the subsequent table may be obtainedfrom(1S,2S)-2-{5-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-ylamino]-pyridin-2-yl}-cyclopropanecarboxylicacid methyl ester (or the corresponding boronic acid thereof) and thebromide (or chloride or iodide) of the respective coupling partnerfollowing the principal procedures described in Step 2 of Intermediate4, Step 2 of Intermediate 11, and Step 1 of Intermediate 14 accompaniedor followed by hydrolysis of the ester group.

Typical procedure for the synthesis of the Examples compiled in thetable below:

A vial charged with a stir bar,(1S,2S)-2-{5-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-ylamino]-pyridin-2-yl}-cyclopropanecarboxylicacid methyl ester (0.064 mmol, 1 equiv.), the coupling partner asbromide, chloride, or iodide (0.076 mmol, 1.2 equiv.), K₃PO₄ (0.159mmol, 2.5 equiv.), water (0.4 mL), and 1,4-dioxane (0.5 mL) is purgedwith Ar for 10 min.Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(PdCl₂(Amphos)₂, 1-5 mol %; alternatively, Pd-PEPPSI-IPent Cl is used ascatalyst) is added, and the mixture is shaken at 80° C. overnight. Aftercooling to room temperature, the mixture is acidified with 50%trifluoroacetic acid and chromatographed (HPLC on reversed phase,acetonitrile/water/trifluoroacetic acid) to afford the title compound astrifluoroacetic acid salt that is optionally transformed into itstrifluoroacetic acid free form.

In case the ester group is not fully saponified after the couplingreaction is complete, the reaction mixture is treated with aqueous 4 MNaOH solution at 50° C. until all the ester is hydrolyzed.

The compounds in the following table are obtained from a 90:10 to97.5:2.5 diastereomeric mixture of(1S,2S)-2-{5-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-ylamino]-pyridin-2-yl}-cyclopropanecarboxylicacid methyl ester and(1R,2R)-2-{5-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-ylamino]-pyridin-2-yl}-cyclopropanecarboxylicacid methyl ester, with the former diastereomer prevailing. The minordiastereomer after the coupling is usually not separated bychromatography resulting in a product mixture of comparablediastereomeric ratio to the one of the starting material.

Ex- R^(L) Retention time on HPLC (method) ample (coupling partner isR^(L)—Br) Mass spectrum (MS) 11

LC(method 1): t_(R) = 0.84 min MS (ESI⁻): m/z = 458 [M − H]⁻ 12

LC (method 1): t_(R) = 0.93 min MS (ESI⁻): m/z = 501 [M − H]⁻ 13

LC (method 1): t_(R) = 0.87 min MS (ESI⁺): m/z = 447 [M + H]⁺ 14

LC (method 1): t_(R) = 0.89 min MS (ESI⁻): m/z = 522 [M − H]⁻ 15

LC (method 1): t_(R) = 0.96 min MS (ESI⁻): m/z = 515 [M − H]⁻ 16

LC (method 1): t_(R) = 0.87 min MS (ESI⁺): m/z = 491 [M + H]⁺ R^(L)—Brused as methyl ester 17

LC (method 1): t_(R) = 0.98 min MS (ESI⁺): m/z = 514 [M + H]⁺ 18

LC (method 1): t_(R) = 0.83 min MS (ESI⁻): m/z = 523 [M − H]⁻ R^(L)—Iused as coupling partner 19

LC (method 1): t_(R) = 0.92 min MS (ESI⁻): m/z = 495 [M − H]⁻ 20

LC (method 1): t_(R) = 0.92 min MS (ESI⁻): m/z = 555 [M − H]⁻ 21

LC (method 1): t_(R) = 0.96 min MS (ESI⁻): m/z = 509 [M + H]⁺ 22

LC (method 1): t_(R) = 0.95 min MS (ESI⁺): m/z = 524 [M + H]⁺ 23

LC (method 1): t_(R) = 0.95 min MS (ESI⁺): m/z = 461 [M + H]⁺ R^(L)—Clas methyl ester used 24

LC (method 1): t_(R) = 0.97 min MS (ESI⁺): m/z = 457/459/461 (2 Cl)([M + H]⁺ R^(L)—I used as coupling partner 25

LC (method 1): t_(R) = 0.92 min MS (ESI⁻): m/z = 452 [M − H]⁻ 26

LC (method 1): t_(R) = 0.98 min MS (ESI⁻): m/z = 529 [M − H]⁻ 27

LC (method 1): t_(R) = 0.84 min MS (ESI⁻): m/z = 472 [M − H]⁻ 28

LC (method 1): t_(R) = 0.88 min MS (ESI⁺): m/z = 525 [M + H]⁺ R^(L)—Iused as coupling partner 29

LC (method 1): t_(R) = 0.89 min MS (ESI⁻): m/z = 522 [M − H]⁻ 30

LC (method 1): t_(R) = 0.93 min MS (ESI⁺): m/z = 499 [M + H]⁺ 31

LC (method 1): t_(R) = 0.95 min MS (ESI⁻): m/z = 455 [M − H]⁻ R^(L)—Iused as coupling partner 32

LC (method 1): t_(R) = 0.97 min MS (ESI⁻): m/z = 515 [M − H]⁻ 33

LC (method 1): t_(R) = 0.94 min MS (ESI⁻): m/z = 501 [M − H]⁻ 34

LC (method 1): t_(R) = 0.93 min MS (ESI⁻): m/z = 503 [M − H]⁻ 35

LC (method 1): t_(R) = min MS (ESI⁻): m/z = 515 [M − H]⁻ 36

LC (method 1): t_(R) = 0.99 min MS (ESI⁺): m/z = 431 [M + H]⁺ 37

LC (method 1): t_(R) = 0.90 min MS (ESI⁺): m/z = 547 [M + H]⁺ 38

LC (method 1): t_(R) = 0.88 min MS (ESI⁺): m/z = 595 [M + H]⁺ 39

LC (method 1): t_(R) = 0.87 min MS (ESI⁺): m/z = 488 [M + H]⁺ 40

LC (method 1): t_(R) = 1.01 min MS (ESI⁺): m/z = 445 [M + H]⁺

The invention claimed is:
 1. A compound of formula (I)

wherein R is selected from the group consisting of H, F, Cl, Br, I,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, NC—,HNR^(N)—C(═O)—, C₁₋₄-alkyl-NR^(N)—C(═O)—, C₃₋₆-cycloalkyl-NR^(N)—C(═O)—,heterocyclyl-NR^(N)—C(═O)—, heteroaryl-NR^(N)—C(═O)—, HOOC—,C₁₋₄-alkyl-O—C(═O)—, O₂N—, HR^(N)N—, C₁₋₄-alkyl-R^(N)N—,C₁₋₄-alkyl-C(═O)NR^(N)—, C₃₋₆-cycloalkyl-C(═O)NR^(N)—,heterocyclyl-C(═O)—NR^(N)—, heteroaryl-C(═O)NR^(N)—,C₁₋₄-alkyl-S(═O)₂NR^(N)—, C₃₋₆-cycloalkyl-S(═O)₂NR^(N)—,heterocyclyl-S(═O)₂NR^(N)—, heteroaryl-S(═O)₂NR^(N)—, HO—,C₁₋₆-alkyl-O—, HOOC—C₁₋₃-alkyl-O—, heterocyclyl-C₁₋₃-alkyl-O—,phenyl-C₁₋₃-alkyl-O—, C₃₋₆-cycloalkyl-O—, heterocyclyl-O—,heteroaryl-O—, C₁₋₄-alkyl-S—, C₃₋₆-cycloalkyl-S—, heterocyclyl-S—,C₁₋₄-alkyl-S(═O)—, C₃₋₆-cycloalkyl-S(═O)—, heterocyclyl-S(═O)—,C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl-S(═O)₂—, heterocyclyl-S(═O)₂—,phenyl-S(═O)₂—, heteroaryl-S(═O)₂—, HNR^(N)—S(═O)₂—,C₁₋₄-alkyl-NR^(N)—S(═O)₂—, heterocyclyl, phenyl, and heteroaryl, whereineach alkyl, cycloalkyl, and heterocyclyl group or sub-group within thegroups forming R is optionally substituted with 1 or more F atoms andoptionally substituted with 1 to 3 groups independently selected fromCl, C₁₋₃-alkyl, NC—, (R^(N))₂N—, HO—, C₁₋₃-alkyl-O—, andC₁₋₃-alkyl-S(═O)₂—; and wherein each phenyl and heteroaryl group orsub-group within the groups forming R is optionally substituted with 1to 5 substituents independently selected from F, Cl, C₁₋₃-alkyl, HF₂C—,F₃C—, NC—, (R^(N))₂N—, HO—, C₁₋₃-alkyl-O—, F₃C—O—, andC₁₋₃-alkyl-S(═O)₂—; wherein each heterocyclyl group or sub-group withinthe groups forming R is selected from a cyclobutyl group wherein 1 CH₂group is replaced by —NR^(N)— or —O—; a C₅₋₆-cycloalkyl group wherein 1CH₂ group is replaced by —C(═O)—, —NR^(N)—, —O— or —S(═O)₂— and/or 1 CHgroup is replaced by N; a C₅₋₆-cycloalkyl group wherein 1 CH₂ group isreplaced by —NR^(N)— or —O—, a second CH₂ group is replaced by —NR^(N)—,—C(═O)— or —S(═O)₂— and/or 1 CH group is replaced by N; and aC₅₋₆-cycloalkyl group wherein 2 CH₂ groups are replaced by —NR^(N)— or 1CH₂ group by —NR^(N)— and the other by —O— and a third CH₂ group isreplaced by —C(═O)— or —S(═O)₂— and/or 1 CH group is replaced by N;wherein each heteroaryl group or sub-group within the groups forming Ris selected from tetrazolyl and a 5- or 6-membered heteroaromatic ringwhich contains 1, 2, or 3 heteroatoms independently of each otherselected from ═N—, —NR^(N)—, —O—, and —S—, wherein in heteroaromaticgroups containing a —HC═N— unit this group is optionally replaced by—NR^(N)—C(═O)—; wherein in heteroaryl and heterocyclyl rings with one ormore NH groups, each of said NH groups is replaced by NR^(N); R¹ isselected from the group consisting of H, F, Cl, C₁₋₄-alkyl,C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkyl, C₁₋₄-alkyl-O—C₁₋₄-alkyl, NC—, HO—,C₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O—, C₁₋₄-alkyl-S—, C₁₋₄-alkyl-S(O)—, andC₁₋₄-alkyl-S(O)₂—, wherein any alkyl and cycloalkyl group or sub-groupwithin the groups forming R¹ is optionally substituted with 1 or more Fatoms, and wherein multiple R¹ may be identical or different if m is 2,3 or 4; m is an integer selected from 1, 2, 3, and 4; R² is selectedfrom the group consisting of H, F, Cl, C₁₋₄-alkyl, NC—, andC₁₋₄-alkyloxy, wherein any alkyl group or sub-group within the groupsforming R² is optionally substituted with 1 or more F atoms, and whereinmultiple R² may be identical or different if n is 2 or 3; R³ is selectedfrom the group consisting of H, F, Cl, C₁₋₄-alkyl, NC—, andC₁₋₄-alkyl-O—, wherein each alkyl group or sub-group within the groupsforming R³ is optionally substituted with 1 or more F atoms; n is aninteger selected from 1, 2, and 3; R^(N) is independently of each otherselected from the group consisting of H, HO—C₁₋₄-alkyl-(H₂C)—,C₁₋₄-alkyl-C(═O)—, C₁₋₄-alkyl-NH—C(═O)—,C₁₋₄-alkyl-N(C₁₋₄-alkyl)-C(═O)—, C₁₋₄-alkyl-O—C(═O)—, andC₁₋₄-alkyl-S(═O)₂, wherein each alkyl group or sub-group within thegroups forming R^(N) is optionally substituted with 1 or more F atoms;wherein in any definition mentioned hereinbefore, if not specifiedotherwise, any alkyl group or sub-group may be straight-chained orbranched, or a salt thereof.
 2. The compound according to claim 1,wherein R is selected from the group consisting of H, F, Cl, C₁₋₆-alkyl,C₃₋₆-cycloalkyl, NC—, HNR^(N)—C(═O)—, C₁₋₄-alkyl-NR^(N)—C(═O)—,C₃₋₆-cycloalkyl-NR^(N)—C(═O)—, heterocyclyl-NR^(N)—C(═O)—, HOOC—, HRNN—,C₁₋₄-alkyl-R^(N)N—, C₁₋₄-alkyl-C(═O)NR^(N)—,C₃₋₆-cycloalkyl-C(═O)NR^(N)—, heterocyclyl-C(═O)NR^(N)—,C₁₋₄-alkyl-S(═O)₂NR^(N)—, HO—, C₁₋₆-alkyl-O—, HOOC—(C₁₋₂-alkyl)-O—,heterocyclyl-C₁₋₂-alkyl-O—, phenyl-C₁₋₂-alkyl-O—, C₃₋₆-cycloalkyl-O—,heterocyclyl-O—, heteroaryl-O—, C₁₋₄-alkyl-S(═O)₂—,C₃₋₆-cycloalkyl-S(═O)₂—, heterocyclyl-S(═O)₂—, HNR^(N)—S(═O)₂—,C₁₋₄-alkyl-NR^(N)—S(═O)₂—, heterocyclyl, and heteroaryl, wherein eachalkyl, cycloalkyl, and heterocyclyl group or sub-group within the groupsforming R is optionally substituted with 1 or more F atoms andoptionally substituted with 1 to 2 groups independently selected fromCl, H₃C—, NC—, R^(N)HN—, HO—, H³C—O—, and H³C—S(═O)²—; wherein eachheteroaryl group or sub-group within the groups forming R is optionallysubstituted with 1 to 3 substituents independently selected from F, Cl,H₃C—, F₃C—, NC—, (R^(N))₂N—, HO—, H₃C—O—, F₃C—O—, and H₃C—S(═O)²—;wherein each heterocyclyl group or sub-group within the groups forming Ris selected from a cyclobutyl group wherein 1 CH₂ group is replaced by—NR^(N)— or —O—; a C₅₋₆-cycloalkyl group wherein 1 CH₂ group is replacedby —C(═O)—, —NR^(N)—, —O— or —S(═O)₂— and/or 1 CH group is replaced byN; a C₅₋₆-cycloalkyl group wherein 1 CH₂ group is replaced by —NR^(N)—or —O—, a second CH₂ group is replaced by —NR^(N)—, —C(═O)— or —S(═O)₂—and/or 1 CH group is replaced by N; wherein each heteroaryl group orsub-group within the groups forming R is selected from tetrazolyl, a5-membered heteroaromatic ring which contains 1, 2 or 3 heteroatomsindependently of each other selected from ═N—, —NH—, O and S, and a6-membered heteroaromatic ring which contains 1 or 2 ═N— atoms, whereina —HC═N— unit is optionally replaced by —NH—C(═O)—; and wherein in eachof the above heteroaryl and heterocyclyl group or sub-group containingone or more NH, said group(s) is replaced by NR^(N); or a salt thereof.3. The compound according to claim 1, wherein R is selected from thegroup consisting of H, F, Cl, H₂NC(═O)—, H₃CNH—C(═O)—, (H₃C)₂N—C(═O)—,HOOC—; C₁₋₃-alkyl optionally substituted with 1 or more F or optionallymonosubstituted with HO—; cyclopropyl optionally monosubstituted withNC—; H₃C—O— optionally monosubstituted with C₁₋₄-alkyl, HOOC—, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, or 1,1-dioxotetrahydrothiopyranyl,wherein the C₁₋₄-alkyl group optionally attached to H₃C—O— is optionallymonosubstituted with NC—, HO— or H₃C—S(═O)₂—, and wherein said oxetanyl,tetrahydrofuranyl, tetrahydropyranyl and 1,1-dioxotetrahydrothiopyranylgroups are optionally monosubstituted with H₃C— or HO—;tetrahydrofuranyl-O— optionally monosubstituted with HO—;tetrahydropyranyl-O—; and a heteroaryl group selected from pyrazolyl,[1,3,4]oxadiazolyl, tetrazolyl, pyridyl, pyridin-2-onyl, pyrazinyl,pyrimidinyl, pyrimidin-2-onyl, and pyrimidin-4-onyl, wherein each ofsaid heteroaryl groups is optionally monosubstituted with H₃C— orH₃C—O—, and wherein each H—N group in said heteroaryl groups isoptionally replaced with H₃C—N or (H₃C)₂C(OH)—H₂C—N; or a salt thereof.4. The compound according to claim 1, wherein R¹ is H, F, Cl, H₃C—,H₃C—H₂C(H₃C)₂CH—, F₃C—, and H₃C—O—; R² is H or F; R³ is H; m is 2 and nis 1; or a salt thereof.
 5. The compound according to claim 1, whereinR¹ is H₃C—; or a salt thereof.
 6. The compound according to claim 1,wherein R is selected from the group consisting of H, F, Cl, H₂NC(═O)—,H₃CNH—C(═O)—, (H₃C)₂N—C(═O)—, HOOC—; C₁₋₃-alkyl optionally substitutedwith 1 or more F or optionally monosubstituted with HO—; cyclopropyloptionally monosubstituted with NC—; H₃C—O— optionally monosubstitutedwith C₁₋₄-alkyl, HOOC—, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,or 1,1-dioxotetrahydrothiopyranyl, wherein the C₁₋₄-alkyl groupoptionally attached to H₃C—O— is optionally monosubstituted with NC—,HO— or H₃C—S(═O)₂—, and wherein said oxetanyl, tetrahydrofuranyl,tetrahydropyranyl and 1,1-dioxotetrahydrothiopyranyl groups areoptionally monosubstituted with H₃C— or HO—; tetrahydrofuranyl-O—optionally monosubstituted with HO—; tetrahydropyranyl-O—; and aheteroaryl group selected from pyrazolyl, [1,3,4]oxadiazolyl,tetrazolyl, pyridyl, pyridin-2-onyl, pyrazinyl, pyrimidinyl,pyrimidin-2-onyl, and pyrimidin-4-onyl, wherein each of said heteroarylgroups is optionally monosubstituted with H₃C— or H₃C—O—, and whereineach H—N group in said heteroaryl groups is optionally replaced withH₃C—N or (H₃C)₂C(OH)—H₂C—N; R¹ is H₃C—; m is 2; R² is H or F; n is 1;and R³ is H; or a salt thereof.
 7. The compound according to claim 1,wherein R is selected from the group consisting of F, Cl, H₃C—,H₃C—H₂C—, (H₃C)₂CH—,

 F₃C—, HOCH₂—, H₂N—C(═O)—, H₃C—NH—C(═O)—, (H₃C)₂N—C(═O)—, HOOC—, H₃C—O—,

wherein the asterisk (-*) indicates the site/point of attachment; R¹ isH₃C—; m is 2; R² is H or F; n is 1; and R³ is H; or a salt thereof. 8.The compound according to claim 1, with the structure andstereochemistry shown in any one of formulae I.1, I.2, I.3, or I.4

or a salt thereof.
 9. A compound selected from the group consisting of:

or a salt thereof.
 10. A pharmaceutically acceptable salt of a compoundaccording to claim
 1. 11. A pharmaceutical composition comprising one ormore compounds according to claim 1 or one or more pharmaceuticallyacceptable salts thereof, optionally together with one or more inertcarriers and/or diluents.
 12. A method for treating diseases orconditions which can be influenced by the modulation of the function ofGPR40 in a patient in need thereof, comprising administering a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof, tothe patient, wherein the treatment is for metabolic diseases orconditions associated with metabolic diseases.
 13. The method of claim12, wherein the treatment is for type 2 diabetes mellitus, insulinresistance, obesity, cardiovascular disease or dyslipidemia.
 14. Apharmaceutical composition comprising one or more compounds according toclaim 1, or one or more pharmaceutically acceptable salts thereof, andone or more additional therapeutic agents, optionally together with oneor more inert carriers and/or diluents.
 15. A pharmaceutical compositionaccording to claim 14 wherein the one or more additional therapeuticagents is selected from the group consisting of antidiabetic agents,agents for the treatment of overweight and/or obesity and agents for thetreatment of high blood pressure, heart failure and/or atherosclerosis.16. A compound with the structure and stereochemistry shown in any oneof the following formulae

wherein R³ is H, R¹ is H or C₁₋₄-alkyl, and LG is Cl, Br, or I, or asalt thereof.
 17. The compound of claim 9 having the structure:


18. The compound of claim 9 having the structure:


19. The compound of claim 9 having the structure:


20. The compound of claim 9 having the structure:


21. The compound of claim 9 having the structure:


22. The compound of claim 9 having the structure:


23. The compound of claim 9 having the structure:


24. The compound of claim 9 having the structure:


25. A salt of the compound of claim 9 having the structure:


26. A salt of the compound of claim 9 having the structure:


27. A salt of the compound of claim 9 having the structure:


28. A salt of the compound of claim 9 having the


29. A salt of the compound of claim 9 having the structure:


30. A salt of the compound of claim 9 having the structure:


31. A salt of the compound of claim 9 having the structure:


32. A salt of the compound of claim 9 having the structure: